An autoimmune stem-like CD8 T cell population drives type 1 diabetes
Open accessAbstract
CD8 T cell-mediated autoimmune diseases result from the breakdown of self-tolerance mechanisms in autoreactive CD8 T cells 1. How autoimmune T cell populations arise and are sustained, and the molecular programmes defining the autoimmune T cell state, are unknown. In type 1 diabetes, β-cell-specific CD8 T cells destroy insulin-producing β-cells. Here we followed the fate of β-cell-specific CD8 T cells in non-obese diabetic mice throughout the course of type 1 diabetes. We identified a stem-like autoimmune progenitor population in the pancreatic draining lymph node (pLN), which self-renews and gives rise to pLN autoimmune mediators. pLN autoimmune mediators migrate to the pancreas, where they differentiate further and destroy β-cells. Whereas transplantation of as few as 20 autoimmune progenitors induced type 1 diabetes, as many as 100,000 pancreatic autoimmune mediators did not. Pancreatic autoimmune mediators are short-lived, and stem-like autoimmune progenitors must continuously seed the pancreas to sustain β-cell destruction. Single-cell RNA sequencing and clonal analysis revealed that autoimmune CD8 T cells represent unique T cell differentiation states and identified features driving the transition from autoimmune progenitor to autoimmune mediator. Strategies aimed at targeting the stem-like autoimmune progenitor pool could emerge as novel and powerful immunotherapeutic interventions for type 1 diabetes.
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21 of 36 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured
- Interpretationown data
A similar model to TCF1hi progenitor CD8 T cells giving rise to TCF1lo differentiated progeny described in chronic viral infections and cancers applies to T1D.
“TCF1hi progenitor CD8 T cells that give rise to TCF1lo differentiated progeny have been described in chronic viral infections and cancers3 and our study reveals that a similar model applies to T1D.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] Philip, M. & Schietinger, A. CD8+ T cell differentiation and dysfunction in cancer. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-021-00574-3 (2021). source
The ‘Late dysfunction molecular programmes’ section reports that TCF1+ progenitor-like cells give rise to TCF1low differentiated cells in chronic viral infection. It also describes TCF1+ early dysfunctional tumour T cells differentiating into TCF1low late dysfunctional cells, but says evidence for a stable tumour-reactive progenitor population is lacking. The citation supports the differentiation pattern in cancer, not the stronger characterization of those tumour cells as established progenitors; the T1D finding is attributed to the citing authors’ own study. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
β-cell-specific CD8 T cells in NOD mice are primed in the pancreatic draining lymph node (pLN) before they infiltrate the pancreas.
“β-cell-specific CD8 T cells in NOD mice are primed in the pancreatic draining lymph node (pLN) before they infiltrate the pancreas6,11.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [6] Anderson, M. S. & Bluestone, J. A. The NOD mouse: a model of immune dysregulation. Annu. Rev. Immunol. 23, 447–485 (2005). source
- cites [11] Ferris, S. T. et al. A minor subset of Batf3-dependent antigen-presenting cells in islets of Langerhans is essential for the development of autoimmune diabetes. Immunity 41, 657–669 (2014). source
The Results report proliferation of β-cell-antigen-specific 8.3 CD8+ T cells in the pancreatic lymph node of NOD mice, and the Discussion describes CD8+ T-cell priming there. The paper does not establish that these CD8+ T cells are primed before infiltrating the pancreas; in the reported transfer experiment, the 8.3 cells did not enter the islets. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Premisecitation
β-cell-specific CD8 T cell responses have notable longevity, as shown by T cell-mediated destruction of islet transplantations in patients with longstanding T1D.
“β-cell-specific CD8 T cell responses have notable longevity, which has been shown by the T cell-mediated destruction of islet transplantations in patients with longstanding T1D23.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [23] Ehlers, M. R. & Rigby, M. R. Targeting memory T cells in type 1 diabetes. Curr. Diab. Rep. 15, 84 (2015). source
The Immunopathology of T1D section describes long-lived autoreactive memory T cells, beta-cell destruction in failed grafts, and antigen-specific CD8+ and CD4+ T cells identified after transplantation. It does not specify that the transplant recipients had longstanding T1D, and it presents the T-cell findings as strong evidence of recurrent autoimmunity rather than direct proof that CD8+ cells alone destroyed the grafts. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
In type 1 diabetes, β-cell-specific CD8 T cells destroy insulin-producing β-cells.
“In type 1 diabetes, β-cell-specific CD8 T cells destroy insulin-producing β-cells.”
- Also stated in: § Abstract · plain
“The pathogenesis of T1D is complex and involves immune cell infiltration of the pancreas: β-cell-specific CD8 T cells destroy insulin-producing β-cells in the pancreatic islets of Langerhans, leading to insulin deficiency and loss of glucose homeostasis4.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [4] Bluestone, J. A., Herold, K. & Eisenbarth, G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464, 1293–1300 (2010). source
The Pathophysiology of type 1 diabetes in mouse and human section (page unavailable) says autoreactive, islet-antigen-reactive T cells play a dominant role in the disease and that CD8+ cells appeared to dominate infiltrates in one study of human pancreases. But it also says the mediators of islet destruction have not been precisely defined; it does not establish that β-cell-specific CD8 T cells directly destroy the β-cells. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Also stated in: § Abstract · plain
- Findingcitation
Based on comparisons of single-cell transcriptomes, pLN TCF1hi AP in T1D have globally distinct gene-expression patterns compared with TCF1hi progenitor exhausted CD8 T cells in chronic viral infection.
“However, based on comparisons of single-cell transcriptomes, pLN TCF1hi AP in T1D have globally distinct gene-expression patterns compared with TCF1hi progenitor exhausted CD8 T cells in chronic viral infection24 (Extended Data Fig. 10).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [24] Yao, C. et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection. Nat. Immunol. 20, 890–901 (2019). source
- Premisecitation
CD8 T cells recognizing the β-cell protein IGRP represent a major pathogenic population in mice and humans.
“CD8 T cells recognizing the β-cell protein islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) represent a major pathogenic population in mice and humans6,8,10.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [6] Anderson, M. S. & Bluestone, J. A. The NOD mouse: a model of immune dysregulation. Annu. Rev. Immunol. 23, 447–485 (2005). source
- cites [8] Tsai, S., Shameli, A. & Santamaria, P. CD8+ T cells in type 1 diabetes. Adv. Immunol. 100, 79–124 (2008). source
- cites [10] Coppieters, K. T. et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J. Exp. Med. 209, 51–60 (2012). source
The Results (Immunohistochemical detection; page unavailable) say IGRP reactivity was the most ubiquitous specificity in the patients’ insulitic lesions. The Discussion says these CD8 T cells may mediate β-cell loss, rather than establishing that IGRP-reactive cells are a major pathogenic population. The mouse passages describe assay optimization using NOD tissue, not the claimed pathogenic role in mice. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
A recent study found that circulating β-cell-specific CD8 T cells in T1D patients are epigenetically distinct from TCM, effector memory T (TEM) cells and exhausted CD8 T cells in chronic infection (for example, in HIV).
“In support of our findings, a recent study found that circulating β-cell–specific CD8 T cells in T1D patients are epigenetically distinct from TCM, effector memory T (TEM) cells and exhausted CD8 T cells in chronic infection26 (for example, in HIV).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [26] Abdelsamed, H. A. et al. Beta cell-specific CD8+ T cells maintain stem cell memory-associated epigenetic programs during type 1 diabetes. Nat. Immunol.21, 578–587 (2020). source
- Findingown data
When analysing the expression-based trajectory of a single shared clone in the pLN, clonal expansion occurred along a similar differentiation path from TCF1hi to TCF1lo as described in Fig. 4a.
“Crucially, when we analysed the expression-based trajectory of a single shared clone in the pLN, we found clonal expansion along a similar differentiation path from TCF1hi to TCF1lo as described in Fig. 4a (Extended Data Fig. 9g).”
Quote in the paperSubstantial claim - Findingown data
Pancreatic TCF1lo cells express significantly more activated caspases 3 and 7 than the pLN populations.
“Pancreatic TCF1lo cells expressed significantly more activated caspases 3 and 7 than the pLN populations”
Quote in the paperNot a substantial claim - Findingown data
IGRP T cells in the pLN segregate into two distinct populations based on TCF1 expression.
“IGRP T cells in the pLN segregated into two distinct populations based on TCF1 expression (Fig. 1e).”
Quote in the paperSubstantial claim - Findingown data
Pancreatic TCF1lo cells are transcriptionally distinct from pLN TCF1lo cells (4,263 DEGs).
“Pancreatic TCF1lo cells were transcriptionally distinct from pLN TCF1lo cells (4,263 DEGs)”
Quote in the paperSubstantial claim - Findingown data
TCF1hi and TCF1lo cells reveal distinct expression patterns of inhibitory molecules, including CD39 and PD1.
“TCF1hi and TCF1lo cells revealed distinct expression patterns of inhibitory molecules (including CD39 and PD1) (Fig. 1g, Extended Data Fig. 2a).”
Quote in the paperNot a substantial claim - Findingown data
All barcodes that expanded in the pancreas were found in the pLN TCF1hi population.
“All barcodes that expanded in the pancreas were found in the pLN TCF1hi population (Extended Data Fig. 9h).”
Quote in the paperSubstantial claim - Findingown data
With each transplant, TCF1hi cells gave rise to stable TCF1hi and TCF1lo populations that persisted for at least five months.
“Notably, with each transplant, TCF1hi cells gave rise to stable TCF1hi and TCF1lo populations that persisted for at least five months (Fig. 3e).”
Quote in the paperSubstantial claim - Findingown data
Donor TCF1hi cells give rise to all three populations (pLN TCF1hi, pLN TCF1lo and pancreatic TCF1lo).
“and gave rise to all three populations (pLN TCF1hi, pLN TCF1lo and pancreatic TCF1lo) (Fig. 3d)”
Quote in the paperSubstantial claim - Findingown data
Effector genes associated with terminal differentiation and apoptosis are shared by TCF1lo populations.
“Effector genes associated with terminal differentiation and apoptosis were shared by TCF1lo populations (Fig. 2d, Extended Data Fig. 3d).”
Quote in the paperNot a substantial claim - Findingown data
pLN TCF1hi cells express numerous Wnt target genes regulating self-renewal and stemness, including Myc, Prickle1 and Axin2.
“Indeed, pLN TCF1hi cells expressed numerous Wnt target genes regulating self-renewal and stemness, including Myc, Prickle1 and Axin2 (Fig. 2b).”
Quote in the paperSubstantial claim - Findingown data
All third hosts became diabetic, even with as few as 20 cells.
“All third hosts became diabetic, even with as few as 20 cells.”
Quote in the paperSubstantial claim - Findingown data
IGRP T cells in the pancreas express low levels of TCF1.
“IGRP T cells in the pancreas expressed low levels of TCF1 (Fig. 1f).”
Quote in the paperNot a substantial claim - Findingown data
Donor TCF1lo cells could not be detected in any tissue.
“By contrast, donor TCF1lo cells could not be detected in any tissue (Fig. 3c, Extended Data Fig. 6b, c).”
Quote in the paperSubstantial claim - Findingown data
IGRP T cells in the pLN and pancreas are antigen-experienced, as shown by their CD44hi phenotype.
“IGRP T cells in the pLN and pancreas were antigen-experienced as shown by their CD44hi phenotype (Fig. 1b)”
Quote in the paperNot a substantial claim - Findingown data
Donor TCF1hi cells can be found in all tissues evaluated.
“Donor TCF1hi cells could be found in all tissues evaluated (Fig. 3c, Extended Data Fig. 6b, c)”
Quote in the paperNot a substantial claim - Findingown data
Genes progressively upregulated from pLN TCF1hi to pLN TCF1lo to pancreatic TCF1lo cells include Entpd1, Gzmb, Id2, Ifng, Lag3 and Pdcd1.
“Genes that became progressively upregulated from pLN TCF1hi to pLN TCF1lo to pancreatic TCF1lo cells included Entpd1, Gzmb, Id2, Ifng, Lag3 and Pdcd1 (group 5; Fig. 2d).”
Quote in the paperSubstantial claim - Findingown data
The phenotypic bifurcation into TCF1hi and TCF1lo populations is unique to IGRP T cells in the pLN, as those in the inguinal LN and spleen express high levels of TCF1 and lack a distinct TCF1loCD39hi population.
“The phenotypic bifurcation into TCF1hi and TCF1lo populations was unique to IGRP T cells in the pLN, as those in the inguinal LN and spleen expressed high levels of TCF1 and lacked a distinct TCF1loCD39hi population (Extended Data Fig. 2b).”
Quote in the paperNot a substantial claim - Findingown data
Polyclonal CD44+CD39+ CD8 T cells in the pLN and pancreas show the same expression pattern for TCF1.
“we found the same expression pattern for TCF1 in polyclonal CD44+CD39+ CD8 T cells in the pLN and pancreas (Extended Data Fig. 2e).”
Quote in the paperNot a substantial claim - Findingown data
Genes uniquely expressed in pLN TCF1hi and progressively lost in pLN and pancreatic TCF1lo populations include genes associated with T cell survival, proliferation and self-renewal.
“Genes that were uniquely expressed in pLN TCF1hi and progressively lost in pLN and pancreatic TCF1lo populations included genes associated with T cell survival, proliferation and self-renewal (groups 1 and 2; Fig. 2d).”
Quote in the paperSubstantial claim - Findingown data
pLN TCF1lo cells display increased expression of genes associated with terminal differentiation and effector function, for example Prdm1, Id2, Fasl, Ifng, Entpd1, Cd38, Tigit and Cish.
“By contrast, pLN TCF1lo cells displayed increased expression of genes associated with terminal differentiation and effector function (for example, Prdm1, Id2, Fasl, Ifng, Entpd1, Cd38, Tigit and Cish) (Fig. 2b).”
Quote in the paperSubstantial claim - Findingown data
IGRP T cells express several inhibitory markers, including PD1, CD38, CD39, LAG3 and TIGIT.
“and expressed several inhibitory markers, including PD1, CD38, CD39, LAG3 and TIGIT (Fig. 1b, Extended Data Fig. 1c).”
Quote in the paperSubstantial claim - Findingown data
In almost all mice, the vast majority of pLN and pancreatic TCF1lo cells harboured clonotypes that were shared with the pLN TCF1hi population.
“In almost all mice, the vast majority of pLN and pancreatic TCF1lo cells harboured clonotypes that were shared with the pLN TCF1hi population”
Quote in the paperSubstantial claim - Findingown data
There are 1,410 differentially expressed genes between pLN TCF1hi and TCF1lo populations.
“We identified 1,410 differentially expressed genes (DEGs) between the pLN TCF1hi and TCF1lo populations”
Quote in the paperNot a substantial claim - Findingown data
IGRP-specific and Insulin B (InsB)-specific CD8 T cells bifurcate into phenotypically similar populations in the pancreatic lymph node.
“IGRP-specific and Insulin B (InsB)-specific CD8 T cells bifurcate into phenotypically similar populations in the pancreatic lymph node.”
Quote in the paperSubstantial claim - Findingown data
Depletion of CD8 T cells prevents type 1 diabetes in 12-week-old female WT NOD mice treated with anti-CD8α depleting antibody for 4 months.
“Depletion of CD8 T cells prevents T1D.”
Quote in the paperSubstantial claim - Findingown data
Bifurcation of IGRP-specific CD8 T cells into TCF1hi and TCF1lo T cell populations is not found in inguinal lymph node or spleen.
“Bifurcation of IGRP-specific CD8 T cells into TCF1hi and TCF1lo T cell populations is not found iLN or spleen.”
Quote in the paperSubstantial claim - Findingown data
IGRP-specific autoimmune CD8 T cell populations are phenotypically and transcriptionally distinct from IGRP-specific effector and memory CD8 T cells generated during acute infections.
“IGRP-specific autoimmune CD8 T cell populations are phenotypically and transcriptionally distinct from IGRP-specific effector and memory CD8 T cells generated during acute infections.”
Quote in the paperSubstantial claim - Findingown data
Donor TCF1hi or TCF1lo 8.3 CD8 T cells were found in pancreatic lymph node and pancreas at 7 days and 19-21 days post transfer into NOD Scid second hosts.
“FACS plots show donor TCF1hi or TCF1lo 8.3 found in pLN and pancreas 7 days (TCF1hi, n = 2; TCF1lo, n = 3) and 19–21 days (TCF1hi, n = 5; TCF1lo, n = 6) post transfer into NOD Scid 2nd hosts.”
Quote in the paperSubstantial claim - Findingown data
Autoimmune NOD pLN IGRP-specific CD8 T cells in type 1 diabetes are distinct from CD8 T cells generated during acute and chronic infections.
“Autoimmune NOD pLN IGRP-specific CD8 T cells in T1D are distinct from CD8 T cells generated during acute and chronic infections.”
Quote in the paperSubstantial claim - Interpretationown data
Pancreatic TCF1lo cells cannot persist in the pancreas without continual replenishment by pLN TCF1hi cells.
“Thus, pancreatic TCF1lo cells cannot persist in the pancreas without continual replenishment by pLN TCF1hi cells.”
Quote in the paperSubstantial claim - Interpretationown data
TCF1lo cells are derived from the reservoir of pLN TCF1hi cells.
“demonstrating that TCF1lo cells are derived from the reservoir of pLN TCF1hi cells (Fig. 4c, d, Extended Data Fig. 9a, b).”
Quote in the paperSubstantial claim - Interpretationown data
Autoimmune IGRP CD8 T cells are distinct from IGRP CD8 T cells generated during infections.
“Thus, autoimmune IGRP CD8 T cells are distinct from IGRP CD8 T cells generated during infections.”
Quote in the paperSubstantial claim - Interpretationown data
The IGRP-specific autoimmune T cell population comprises three distinct T cell subsets: pLN TCF1hi, pLN TCF1lo and pancreatic TCF1lo cells.
“Thus, the IGRP-specific autoimmune T cell population comprises three distinct T cell subsets: pLN TCF1hi, pLN TCF1lo and pancreatic TCF1lo cells.”
Quote in the paperSubstantial claim - Interpretationown data
pLN TCF1lo cells continue to differentiate in the pancreas.
“indicating that pLN TCF1lo cells continue to differentiate in the pancreas (Fig. 2c).”
Quote in the paperSubstantial claim - Interpretationown data
Donor TCF1lo cells probably undergo apoptosis after transfer into new hosts.
“suggesting that donor TCF1lo cells probably undergo apoptosis after transfer into new hosts (Extended Data Fig. 6d).”
Quote in the paperSubstantial claim - Interpretationown data
Phenotypic bifurcation in the pLN appears to be a key feature of the β-cell-specific CD8 T cell repertoire.
“Thus, phenotypic bifurcation in the pLN appears be a key feature of the β-cell-specific CD8 T cell repertoire.”
Quote in the paperSubstantial claim - Interpretationown data
Changes in trafficking and spatial orientation within the pLN might be associated with the transition from TCF1hi to TCF1lo cells.
“Many of the genes exhibiting the largest changes in expression were associated with migration, suggesting that changes in trafficking and spatial orientation within the pLN might be associated with the transition from TCF1hi to TCF1lo cells (Extended Data Fig. 8d).”
Quote in the paperNot a substantial claim - Interpretationown data
A subset of clones from the diverse pLN TCF1hi repertoire give rise to the majority of pathogenic T cells in the pancreas.
“Thus, a subset of clones from the diverse pLN TCF1hi repertoire give rise to the majority of pathogenic T cells in the pancreas.”
Quote in the paperSubstantial claim - Interpretationown data
Single-cell RNA-seq of pLN IGRP-specific (NRP-V7+) CD8 T cells reveals intermediate cell states during differentiation of pLN TCF1hi to pLN TCF1lo cells.
“Single cell (sc) RNA-seq of pLN IGRP-specific (NRP-V7+) CD8 T cells reveals intermediate cell states during differentiation of pLN TCF1hi to pLN TCF1lo cells.”
Quote in the paperSubstantial claim - Interpretationreasoning
The authors' data suggest that long-term protection by anti-CD3 could be due to targeting of progenitor populations, either through depletion, tolerance induction or other cell-intrinsic modulation.
“our data suggest that this could be due to the targeting of progenitor populations, either through depletion, tolerance induction or other cell-intrinsic modulation.”
Quote in the paperSubstantial claim - Interpretationown data
The authors' work reveals how fate diversification of stem-like CD8 T cells initiates and sustains T1D.
“In sum, our work reveals how fate diversification of stem-like CD8 T cells initiates and sustains T1D.”
Quote in the paperSubstantial claim - Interpretationown data
The progeny of TCF1hi progenitors in chronic viral infection (TOX+KLRG1+ exhausted cells) and TCF1hi AP in T1D (TOX−KLRG1− cytotoxic AM) are phenotypically, transcriptionally and functionally distinct.
“Notably, the progeny of TCF1hi progenitors in chronic viral infection (TOX+KLRG1+ exhausted cells) and TCF1hi AP in T1D (TOX−KLRG1− cytotoxic AM) are phenotypically, transcriptionally and functionally distinct.”
Quote in the paperSubstantial claim - Interpretationcitation
TCF1hi AP are also distinct from MPEC and TCM generated during acute infections.
“TCF1hi AP are also distinct from MPEC and TCM generated during acute infections25 (Extended Data Figs. 4, 10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Schauder, D. M. et al. E2A-regulated epigenetic landscape promotes memory CD8 T cell differentiation. Proc. Natl Acad. Sci. USA 118, e2013452118 (2021). source
- Interpretationown data
Autoimmune CD8 T cells in T1D represent unique T cell differentiation states distinct from previously described CD8 T cell populations in infections and cancer.
“Thus, our work reveals that autoimmune CD8 T cells in T1D represent unique T cell differentiation states distinct from previously described CD8 T cell populations in infections and cancer.”
Quote in the paperSubstantial claim - Interpretationown data
scTCR-Seq and genetic barcoding experiments reveal derivation of IGRP-specific pancreatic T cells from the pLN TCF1hi population.
“scTCR-Seq and genetic barcoding experiments reveal derivation of IGRP-specific pancreatic T cells from pLN TCF1hi population.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 16
- May combine two claims. 27
Classified as probably not a substantial claim.
PremisecitationCD8 T cell-mediated autoimmune diseases result from the breakdown of self-tolerance mechanisms in autoreactive CD8 T cells.
“CD8 T cell-mediated autoimmune diseases result from the breakdown of self-tolerance mechanisms in autoreactive CD8 T cells1.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] Bluestone, J. A., Bour-Jordan, H., Cheng, M. & Anderson, M. T cells in the control of organ-specific autoimmunity. J. Clin. Invest. 125, 2250–2260 (2015). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationT1D becomes clinically evident when the majority (over 80%) of β-cells have been destroyed, requiring a prolonged latent period of β-cell killing over time (months to years in humans).
“T1D becomes clinically evident when the majority (over 80%) of β-cells have been destroyed, requiring a prolonged latent period of β-cell killing over time (months to years in humans)5.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] Herold, K. C., Vignali, D. A., Cooke, A. & Bluestone, J. A. Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nat. Rev. Immunol. 13, 243–256 (2013). source
The paper’s opening discussion (page unavailable in our copy) describes a long prediabetic period during which β cells are killed over many years. But it says that as much as 30% of β-cell mass may remain at onset, so it does not support the claim that clinical disease requires destruction of over 80%. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationThe non-obese diabetic (NOD) mouse model is a clinically relevant model of T1D and shares many features with the human disease, including spontaneous CD4 and CD8 T cell responses to many of the same β-cell antigens.
“The non-obese diabetic (NOD) mouse model is a clinically relevant model of T1D6,7 and shares many features with the human disease, including spontaneous CD4 and CD8 T cell responses to many of the same β-cell antigens6–9.”
Quote in the paperSubstantial claim2 of 4 sources checked- cites [6] Anderson, M. S. & Bluestone, J. A. The NOD mouse: a model of immune dysregulation. Annu. Rev. Immunol. 23, 447–485 (2005). source
- cites [7] Unanue, E. R. Antigen presentation in the autoimmune diabetes of the NOD mouse. Annu. Rev. Immunol. 32, 579–608 (2014). source
The Introduction and Conclusions describe NOD mice as a spontaneous model of T1D with important similarities to human disease. The Diabetogenic CD4 T Cells section reports broad β-cell autoreactivity and identifies both CD4 and CD8 T cells in NOD mice; Human Studies also reports insulin-reactive T cells in people with T1D. But the paper does not establish spontaneous CD4 and CD8 responses to many of the same β-cell antigens in both species, and the Conclusions explicitly leave the human counterpart of a described NOD CD4 response as an open question. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [8] Tsai, S., Shameli, A. & Santamaria, P. CD8+ T cells in type 1 diabetes. Adv. Immunol. 100, 79–124 (2008). source
- cites [9] Zakharov, P. N., Hu, H., Wan, X. & Unanue, E. R. Single-cell RNA sequencing of murine islets shows high cellular complexity at all stages of autoimmune diabetes. J. Exp. Med. 217, e20192362 (2020). source
The Introduction describes NOD diabetes as chronic and similar to human T1D, and the Discussion says both have CD4 and CD8 T cells in their islets. The Discussion reports responses to insulin and other β-cell antigens in NOD mice, but says this study did not determine T-cell specificity; it does not establish that mouse and human T cells respond to many of the same antigens. No page numbers are available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHaematopoietic, somatic and cancer stem cells in mice and humans have been identified via serial transplantation of limiting cell numbers into immunodeficient mice.
“Haematopoietic19, somatic14 and cancer stem cells20 in mice and humans have been identified via serial transplantation of limiting cell numbers into immunodeficient mice.”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [19] Graef, P. et al. Serial transfer of single-cell-derived immunocompetence reveals stemness of CD8+ central memory T cells. Immunity 41, 116–126 (2014). source
The Discussion describes this study’s serial single-cell transfers as modeled on hematopoietic stem-cell studies, and the Results compare its recovery rate with that of single hematopoietic stem cells. Those passages support the hematopoietic analogy, but do not establish the claimed use of immunodeficient mice to identify hematopoietic stem cells in both mice and humans. The separately cited somatic and cancer stem-cell claims are not assessed here. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [14] van Loosdregt, J. & Coffer, P. J. The role of WNT signaling in mature T cells: T cell factor is coming home. J. Immunol. 201, 2193–2200 (2018). source
- cites [20] Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994). source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationIn autoimmunity, self-reactive T cells acquire cytotoxic effector functions and cause destruction of self.
“In autoimmunity, self-reactive T cells acquire cytotoxic effector functions and cause destruction of self1.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [1] Bluestone, J. A., Bour-Jordan, H., Cheng, M. & Anderson, M. T cells in the control of organ-specific autoimmunity. J. Clin. Invest. 125, 2250–2260 (2015). source
The Conclusion (Figure 1; page unavailable) says autoreactive T cells are more prone to activation in autoimmune disease and that autoreactive ex-Foxp3 cells may contribute to tissue destruction. It describes those cells producing pro-inflammatory cytokines, but does not establish that self-reactive T cells acquire cytotoxic effector functions as the claim specifies. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTOX has been described as a key driver of CD8 T cell exhaustion in tumours and chronic infections, settings of persistent antigen encounter.
“TOX has been described as a key driver of CD8 T cell exhaustion in tumours and chronic infections, settings of persistent antigen encounter3.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [3] Philip, M. & Schietinger, A. CD8+ T cell differentiation and dysfunction in cancer. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-021-00574-3 (2021). source
Classified as probably not a substantial claim.
PremisecitationTCF1hi progenitor CD8 T cells that give rise to TCF1lo differentiated progeny have been described in chronic viral infections and cancers.
“TCF1hi progenitor CD8 T cells that give rise to TCF1lo differentiated progeny have been described in chronic viral infections and cancers3”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] Philip, M. & Schietinger, A. CD8+ T cell differentiation and dysfunction in cancer. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-021-00574-3 (2021). source
The ‘Late dysfunction molecular programmes’ section says that TCF1+ progenitor-like CD8+ T cells give rise to TCF1low differentiated cells during chronic viral infection. For cancer, it describes TCF1+ early dysfunctional tumour-infiltrating cells differentiating into TCF1low late dysfunctional cells, but says evidence for a stable population of tumour-reactive TCF1+ progenitors within tumours is lacking. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationIn cancers or chronic viral infections, contexts in which T cells encounter persistent antigen, T cells enter a hyporesponsive state generally referred to as T cell exhaustion or dysfunction.
“In cancers or chronic viral infections, contexts in which T cells encounter persistent antigen, T cells enter a hyporesponsive state generally referred to as T cell exhaustion or dysfunction3.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] Philip, M. & Schietinger, A. CD8+ T cell differentiation and dysfunction in cancer. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-021-00574-3 (2021). source
Classified as probably not a substantial claim.
PremisecitationThe gold-standard assay to evaluate stem cell functions remains serial transplantation in animal models.
“The gold-standard assay to evaluate stem cell functions remains serial transplantation in animal models.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [19] Graef, P. et al. Serial transfer of single-cell-derived immunocompetence reveals stemness of CD8+ central memory T cells. Immunity 41, 116–126 (2014). source
- cites [14] van Loosdregt, J. & Coffer, P. J. The role of WNT signaling in mature T cells: T cell factor is coming home. J. Immunol. 201, 2193–2200 (2018). source
- cites [20] Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994). source
Classified as probably not a substantial claim.
PremisecitationAnti-CD3 treatment (teplizumab) has been shown to induce long-term protection (currently up to six years) from T1D in at-risk individuals.
“Moreover, anti-CD3 treatment (teplizumab) has been shown to induce long-term protection (currently up to six years) from T1D in at-risk individuals, but the mechanisms responsible for this long-term protection remain incompletely understood29,30”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [29] Herold, K. C. et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N. Engl. J. Med. 381, 603–613 (2019). source
The Results (Efficacy; page not provided) show that teplizumab delayed diagnosis of type 1 diabetes in high-risk relatives, and the Discussion reports a median delay of two years. The paper does not establish protection lasting six years: median follow-up was 745 days, although the longest follow-up was 2683 days (Results, Participants; page not provided). It describes delayed progression, not prevention of diabetes. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [30] Sims, E. K. et al. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Sci. Transl. Med. 13, eabc8980 (2021). source
The Results section reports a sustained delay in T1D among high-risk relatives treated with teplizumab; eight treated participants followed beyond five years remained undiagnosed. It does not establish protection specifically through six years, and describes delayed diagnosis rather than permanent prevention. Page numbers were not provided in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn acute infections, antigen-specific CD8 T cells differentiate into functional cytotoxic effector and memory T cells.
“In acute infections, antigen-specific CD8 T cells differentiate into functional cytotoxic effector and memory T cells2.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [2] Kaech, S. M. & Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12, 749–761 (2012). source
Classified as probably not a substantial claim.
PremisecitationTCF1 is a transcription factor critical for T cell memory, longevity and self-renewal.
“TCF1 is a transcription factor critical for T cell memory, longevity and self-renewal13.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [13] Escobar, G., Mangani, D. & Anderson, A. C. T cell factor 1: a master regulator of the T cell response in disease. Sci Immunol 5, eabb9726 (2020). source
May combine two claims.
Findingown dataThe pLN TCF1hi population is highly clonally diverse compared with the pLN and pancreas TCF1lo populations and contains an abundance of rare, unexpanded clones that are exclusive to the pLN TCF1hi pool.
“The pLN TCF1hi population was highly clonally diverse compared with the pLN and pancreas TCF1lo populations and contained an abundance of rare, unexpanded clones that were exclusive to the pLN TCF1hi pool (Fig. 4e, Extended Data Fig. 9c–e).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCells with high and low expression of Tcf7 are at opposite ends of the trajectory; Tcf7hi cells display a stem-like transcriptional program, whereas Tcf7lo cells harbour a terminally differentiated and cytotoxic program.
“Clustering and trajectory analyses revealed that cells with high and low expression of Tcf7 were at opposite ends of the trajectory; Tcf7hi cells displayed a stem-like transcriptional program, whereas Tcf7lo cells harboured a terminally differentiated and cytotoxic program (Fig. 4a, b, Extended Data Fig. 8a–d).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDonor 8.3 cells bifurcate into TCF1hiCD39lo and TCF1loCD39hi populations in the pLN, whereas only TCF1loCD39hi T cells emerge in the pancreas, recapitulating the same phenotypes of endogenous IGRP CD8 T cells in wild-type NOD mice.
“Donor 8.3 cells bifurcated into TCF1hiCD39lo and TCF1loCD39hi populations in the pLN, whereas only TCF1loCD39hi T cells emerged in the pancreas, recapitulating the same phenotypes of endogenous IGRP CD8 T cells in wild-type NOD mice (Extended Data Fig. 5b–d).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFTY720-treated mice lost half of the initial pancreatic CD8 T cell population, whereas control mice had significantly more CD8 T cells in the pancreas compared with the beginning of treatment.
“FTY720-treated mice lost half of the initial pancreatic CD8 T cell population, whereas control mice had significantly more CD8 T cells in the pancreas compared with the beginning of treatment (Fig. 3h, Extended Data Fig. 6e–g).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNOD/SCID hosts that received pLN TCF1hi cells became diabetic whereas hosts that received TCF1lo cells did not.
“NOD/SCID hosts that received pLN TCF1hi cells became diabetic whereas hosts that received TCF1lo cells did not (Fig. 3b, Extended Data Fig. 6a).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIntermediate cell states along the trajectory retained Tcf7 expression but lost some stemness-associated genes and upregulated genes associated with the Tcf7lo cluster.
“We identified intermediate cell states along the trajectory, which retained Tcf7 expression but lost some stemness-associated genes and upregulated genes associated with the Tcf7lo cluster (Fig. 4a, b, Extended Data Fig. 8b–f).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHigh Sell (CD62L) and Entpd1 (CD39) RNA transcript and protein expression mark the opposite ends of the differentiation trajectory, while intermediate cell states do not express Sell (or CD62L) or Entpd1 (or CD39).
“High Sell (which encodes CD62L) and Entpd1 (which encodes CD39) RNA transcript and protein expression marked the opposite ends of the differentiation trajectory, while intermediate cell states did not express Sell (or CD62L) or Entpd1 (or CD39).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataInsulin B-chain-specific CD8 T cells also bifurcate into distinct TCF1hiCD39loPD1lo and TCF1loCD39hiPD1hi populations in the pLN and display a consistently TCF1loCD39hiPD1hi phenotype in the pancreas.
“Insulin B-chain-specific CD8 T cells also bifurcated into distinct TCF1hiCD39loPD1lo and TCF1loCD39hiPD1hi populations in the pLN and displayed a consistently TCF1loCD39hiPD1hi phenotype in the pancreas (Extended Data Fig. 2c, d).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMice treated with FTY720 were completely protected from T1D and had significantly reduced insulitis compared with control mice.
“Mice treated with FTY720 were completely protected from T1D and had significantly reduced insulitis compared with control mice (Fig. 3f, g).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataBy 15-20 weeks, approximately 80% of NOD mice in the authors' colony have developed T1D.
“by which time approximately 80% of NOD mice in our colony have developed T1D (Extended Data Fig. 1b).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAs few as 100 TCF1hi cells were sufficient to induce T1D, whereas as many as 100,000 TCF1lo cells were not.
“Even as few as 100 TCF1hi cells were sufficient to induce T1D, whereas as many as 100,000 TCF1lo cells were not (Fig. 3b).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDespite expression of inhibitory markers, IGRP T cells are highly functional and produce high levels of IFNγ and TNF upon ex vivo stimulation.
“Despite the expression of these inhibitory markers, IGRP T cells were highly functional and produced high levels of IFNγ and TNF upon ex vivo stimulation (Fig. 1c).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTCF1hi and TCF1lo cells comprise approximately 80% and 20% of the IGRP-specific population in the pLN, respectively, and can be identified as early as 5 weeks of age and persist throughout disease progression and mouse lifespan (25 to 30 weeks).
“TCF1hi and TCF1lo cells, comprising approximately 80% and 20% of the IGRP-specific population, respectively, could be identified in the pLN as early as 5 weeks of age, and persisted throughout disease progression and mouse lifespan (25 to 30 weeks).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGSEA and gene ontology classification show pLN TCF1hi cells are enriched for pathways involved in MYC and E2F signalling and DNA replication, whereas pLN TCF1lo cells are enriched for pathways associated with T cell activation, cytotoxicity and apoptosis.
“Gene set enrichment analyses (GSEA) and gene ontology classification showed that pLN TCF1hi cells were enriched for pathways involved in MYC and E2F signalling and DNA replication, whereas pLN TCF1lo cells were enriched for pathways associated with T cell activation, cytotoxicity and apoptosis (Extended Data Fig. 3b, c).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSelect clones shared between the pLN TCF1hi and other populations expanded significantly in size upon downregulation of TCF1; consequently, the majority of clonotypes found in TCF1lo cells were shared with the TCF1hi population.
“The select clones that were shared between the pLN TCF1hi and other populations expanded significantly in size upon downregulation of TCF1; consequently, the majority of clonotypes found in TCF1lo cells were shared with the TCF1hi population (Extended Data Fig. 9f).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datapLN IGRP T cells express moderate levels of TOX and pancreatic IGRP T cells express minimal levels of TOX, in contrast to exhausted and dysfunctional T cells in chronic viral infections and tumours.
“pLN IGRP T cells expressed moderate levels of TOX and pancreatic IGRP T cells expressed minimal levels of TOX, in contrast to exhausted and dysfunctional T cells in chronic viral infections and tumours (Fig. 1d, Extended Data Fig. 1d).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIGRP-specific CD8 T cells can be found in the pLN and pancreas as early as 5 weeks of age, and their frequency increases over time, peaking at around 0.3% and 20% of CD8 T cells in the pLN and pancreas by 15-20 weeks, respectively.
“IGRP-specific CD8 T cells (hereafter referred to as IGRP T cells) can be found in the pLN and pancreas as early as 5 weeks of age, and their frequency increases over time, peaking at around 0.3% and 20% of CD8 T cells in the pLN and pancreas by 15–20 weeks, respectively”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataTransferred donor T cells were not detected in pancreas before day 12 after transfer into NOD Scid hosts.
“(note: transferred donor T cells were not detected in pancreas before day 12)”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown datapLN TCF1hi cells can both self-renew and produce differentiated progeny.
“demonstrating that pLN TCF1hi cells can both self-renew and produce differentiated progeny.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAlthough CD4 T cells initiate pancreatic infiltration and provide help to CD8 T cells, the CD8 T cells are primarily responsible for β-cell destruction.
“Although CD4 T cells initiate pancreatic infiltration and provide help to CD8 T cells, the CD8 T cells primarily responsible for β-cell destruction8”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Tsai, S., Shameli, A. & Santamaria, P. CD8+ T cells in type 1 diabetes. Adv. Immunol. 100, 79–124 (2008). source
May combine two claims.
InterpretationreasoningAP are necessary to generate and replenish the pool of pancreatic AM, which are short-lived and thus unable to independently sustain the prolonged β-cell destruction that causes T1D.
“AP are necessary to generate and replenish the pool of pancreatic AM, which are short-lived and thus unable to independently sustain the prolonged β-cell destruction that causes T1D.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe induction and maintenance of diabetogenic T cell responses requires two functionally distinct populations: short-lived pancreatic AM to destroy β-cells and self-renewing pLN AP to replenish the AM population, thereby enabling sustained β-cell damage that culminates in T1D.
“We propose that the induction and maintenance of diabetogenic T cell responses requires two functionally distinct populations: short-lived pancreatic AM to destroy β-cells and self-renewing pLN AP to replenish the AM population, thereby enabling sustained β-cell damage that culminates in T1D.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown datapLN TCF1hi cells represent a stem-like autoimmune progenitor (AP) population that self-renews long-term and gives rise to terminally differentiated pancreatic TCF1lo autoimmune mediators (AM) that destroy β-cells.
“In conclusion, pLN TCF1hi cells represent a stem-like autoimmune progenitor (AP) population that self-renews long-term and gives rise to terminally differentiated pancreatic TCF1lo autoimmune mediators (AM) that destroy β-cells (Fig. 4f).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNo statistical methods were used to pre-determine sample size.
“No statistical methods were used to pre-determine sample size.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe investigators were not blinded to allocation during experiments and outcome assessment.
“The investigators were not blinded to allocation during experiments and outcome assessment.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTCF1 is one of the targets of canonical Wnt signalling, which maintains stemness in adult tissue stem cells, tumours, and peripheral T cells.
“TCF1 is one of the targets of canonical Wnt signalling, which maintains stemness in adult tissue stem cells, tumours, and peripheral T cells14,15.”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationFTY720 is a sphingosine-1-phosphate receptor agonist that blocks lymph node egress and has been shown to protect NOD mice from T1D.
“FTY720, a sphingosine-1-phosphate receptor agonist that blocks lymph node egress and has been shown to protect NOD mice from T1D21,22”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [21] Maki, T., Gottschalk, R., Ogawa, N. & Monaco, A. P. Prevention and cure of autoimmune diabetes in nonobese diabetic mice by continuous administration of FTY720. Transplantation 79, 1051–1055 (2005). source
- cites [22] Brinkmann, V. et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov. 9, 883–897 (2010). source
May combine two claims.
Interpretationown dataStem-like functionality of pLN TCF1hi CD8 T cells and generation of differentiated TCF1lo CD8 T cells are independent of lymphopenic conditions.
“Stem-like functionality of pLN TCF1hi CD8 T cells and generation of differentiated TCF1lo CD8 T cells are independent of lymphopenic conditions.”
Quote in the paperSubstantial claim
The paper relies on this without support.
How autoimmune T cell populations arise and are sustained, and the molecular programmes defining the autoimmune T cell state, are unknown.
“How autoimmune T cell populations arise and are sustained, and the molecular programmes defining the autoimmune T cell state, are unknown.”
The paper relies on this without support.
Despite presumed chronic self-antigen exposure on normal tissues, autoimmune T cells do not become dysfunctional, but retain effector functions and progressively destroy the tissue.
“Despite presumed chronic self-antigen exposure on normal tissues, autoimmune T cells do not become dysfunctional, but retain effector functions and progressively destroy the tissue.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Exhausted CD8 and CD4 T cells are present in inflamed tissues of T1D and SLE models.
“and exhausted CD8 and CD4 T cells are present in inflamed tissues of T1D 36,62 and systemic lupus erythematosus (SLE) 63 models.”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [62]
The Abstract says autoimmune T cells retain effector function rather than becoming dysfunctional. In “Phenotype of IGRP-specific CD8 T cells” (page unavailable), pancreatic CD8 T cells have minimal TOX expression, in contrast to exhausted T cells. This source therefore makes a contrary point about CD8 cells in the T1D model; it does not establish the sentence’s CD4 or SLE claims. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting accession numbers for the acute and chronic infection dataset
MinorThe Methods identify the day-7 acute and chronic infection data as GEO accession GSE119940, while Data availability identifies the corresponding published dataset as GSE119943.
“Gene count matrices for day 7 CD8 T cells from acute and chronic infection were obtained from GEO (GSE119940)”
“Comparisons to publicly available published data used the following datasets: GSE11994324, GSE13013025 and GSE7081356.”
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- Authors
- Gearty, S. V., Dündar, F., Zumbo, P., Espinosa-Carrasco, G., Shakiba, M., Sanchez-Rivera, F. J., Socci, N. D., Trivedi, P., Lowe, S. W., Lauer, P., Mohibullah, N., Viale, A., DiLorenzo, T. P., Betel, D., & Schietinger, A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Weill Cornell Medicine (US)
- Aduro BioTech (United States) (US)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Betel, Doron
- Schietinger, Andrea
- ORCID
- Venue
- Nature
- Published
- 2021-11-30
- Volume
- 602
- Issue
- 7895
- Pages
- 156-161
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9315050
- OpenAlex
- W3216791550
- Cited by
- 257
- References
- 56
- Citations by year
- 2026: 52 · 2025: 74 · 2024: 61 · 2023: 45 · 2022: 25
- FWCI
- 18.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (T32CA160001, DP2CA225212, P30CA008748)
- National Institute of General Medical Sciences (T32GM007739)
- National Institute of Allergy and Infectious Diseases (R01AI123730)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK052956, F30DK122691, P30DK020541)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- type 1 diabetes, CD8+ T cells, beta cell destruction, self-renewal, NOD mice, immunotherapy, autoimmunity
- MeSH terms
- Cell Self Renewal, Animals, Clone Cells, Diabetes Mellitus, Type 1, Disease Models, Animal, Female, Glucose-6-Phosphatase, Lymph Nodes, Male, Receptors, Antigen, T-Cell, Stem Cells, CD8-Positive T-Lymphocytes, Stem Cell Transplantation, Insulin-Secreting Cells, Mice, Hepatocyte Nuclear Factor 1-alpha, Single-Cell Analysis, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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