CoChat
Sign Up
Cited by 164Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsCancer-related Molecular Pathways

p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes

Open access
Mondal, Abdul M., Horikawa, Izumi, Pine, Sharon R., Fujita, Kaori, Morgan, Katherine M., Vera, Elsa, Mazur, Sharlyn J., Appella, Ettore +4 more·2013·Journal of Clinical Investigation
DOI 10.1172/jci70355PMC PMC3859419
Open this paper in CoChat — free accountOpen PDF

Abstract

Cellular senescence contributes to aging and decline in tissue function. p53 isoform switching regulates replicative senescence in cultured fibroblasts and is associated with tumor progression. Here, we found that the endogenous p53 isoforms Δ133p53 and p53β are physiological regulators of proliferation and senescence in human T lymphocytes in vivo. Peripheral blood CD8+ T lymphocytes collected from healthy donors displayed an age-dependent accumulation of senescent cells (CD28-CD57+) with decreased Δ133p53 and increased p53β expression. Human lung tumor-associated CD8+ T lymphocytes also harbored senescent cells. Cultured CD8+ blood T lymphocytes underwent replicative senescence that was associated with loss of CD28 and Δ133p53 protein. In poorly proliferative, Δ133p53-low CD8+CD28- cells, reconstituted expression of either Δ133p53 or CD28 upregulated endogenous expression of each other, which restored cell proliferation, extended replicative lifespan and rescued senescence phenotypes. Conversely, Δ133p53 knockdown or p53β overexpression in CD8+CD28+ cells inhibited cell proliferation and induced senescence. This study establishes a role for Δ133p53 and p53β in regulation of cellular proliferation and senescence in vivo. Furthermore, Δ133p53-induced restoration of cellular replicative potential may lead to a new therapeutic paradigm for treating immunosenescence disorders, including those associated with aging, cancer, autoimmune diseases, and HIV infection.

Integrity signals

Registry

Crossref · 10.1172/jci70355

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 46 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Tumor-associated CD8+ T lymphocytes from lung cancer tissues contained CD28+CD57- (mean 60.3% ± 12.7%) and CD28-CD57+ (mean 8.7% ± 6.7%) subsets.

    “A considerable fraction of CD28 + CD57 - (mean, 60.3% ± 12.7%) and CD28 -CD57 + (mean, 8.7% ± 6.7%) subsets were observed in the tumor-associated CD8 + T lymphocytes, similar to blood T lymphocytes (Supplemental Tables 1 and 2).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In donors 1 and 2, Δ133p53 expression decreased from the CD28+CD57- subset through CD28+CD57+, CD28-CD57-, and CD28-CD57+ subsets.

    “In donors 1 and 2, in which all 4 quadrants were examined, Δ133p53 expression was decreased from the CD28 + CD57 -(most proliferative) subset to the CD28 + CD57 + , CD28 -CD57 -, and CD28 -CD57 + (senescent) subsets (Figure 2A).”
    Quote in the paperSubstantial claim
  • Findingown data

    p53β expression in the CD28-CD57+ subset was 1.23- to 2.06-fold (average 1.72-fold) higher than in the CD28+CD57- subset.

    “In contrast, the expression level of p53β in the CD28 -CD57 + subset was 1.23-to 2.06-fold (average, 1.72-fold) higher than that in the CD28 + CD57 -subset (P = 0.0020; Figure 2, A and B).”
    Quote in the paperSubstantial claim
  • Findingown data

    Elevated p53β protein in senescent CD28-CD57+ subsets was associated with increased p53β mRNA.

    “The elevated levels of p53β protein in the senescent CD28 -CD57 + subsets were associated with increased p53β mRNA levels (Figure 2C and Supplemental Figure 5E).”
    Quote in the paperSubstantial claim
  • Findingown data

    Across all 6 donors examined, Δ133p53 expression in the CD28-CD57+ subset was 1%-22% (average 10%) of that in the CD28+CD57- subset.

    “In all 6 donors examined, the expression level of Δ133p53 in the CD28 -CD57 + subset was 1%-22% (average, 10%) of that in the CD28 + CD57 -subset (P < 0.0001; Figure 2, A and B).”
    Quote in the paperSubstantial claim
  • May combine two claims. 45
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingown data

    When CD28 and CD57 were analyzed separately, CD8+ T lymphocytes tended to lose CD28 and gain CD57 with donor age.

    “Consistently, when CD28 and CD57 were separately analyzed, CD8 + T lymphocytes tended to lose CD28 (r = -0.8224;P < 0.0001) and gain CD57 (r = 0.5813; P < 0.0001) expression as a function of donor age”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Bafilomycin A1 upregulated the reduced Δ133p53 levels in CD28-CD57+ subsets approximately 2- to 3-fold in all 3 cases examined, while not affecting abundant Δ133p53 in CD28+CD57- subsets.

    “While the abundant levels of Δ133p53 in CD28 + CD57 -subsets were not affected by this treatment, the reduced levels of Δ133p53 in CD28 -CD57 + subsets were upregulated approximately 2-to 3-fold in response to bafilomycin A1 in all 3 cases examined.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The CD28-CD57+ subset showed increased HP1-γ foci, spontaneous γ-H2AX foci, and mRNA for SASP factors IL6, IL8, CXCR1, and CXCR2.

    “Other senescence markers previously used with other cell types, including formation of HP1-γ foci (28,29), spontaneous induction of γ-H2AX foci (30), and mRNA expression of SASP factors, such as IL6, IL8, CXCR1, and CXCR2 (8), were also increased in the CD28 -CD57 + subset”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [28] source

      Not checked in the free run.

    • cites [29] source

      Not checked in the free run.

    • cites [30] source

      Not checked in the free run.

    • cites [8] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    No or weaker age association was found for the CD28+CD57+ and CD28-CD57- subsets.

    “while no or weaker association was found in the CD28 + CD57 + (r = -0.0953;P = 0.7883) or CD28 -CD57 -(r = 0.3934; P = 0.0019) subsets (Supplemental Figure 1B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among FACS-sorted CD28/CD57 quadrants, the CD28+CD57- subset had the highest proliferation rate, while the CD28-CD57+ subset had the lowest.

    “The CD28 + CD57 -subset, which decreased with age, showed the highest proliferation rate (proliferation index, 2.61 ± 0.23), while the CD28 -CD57 + subset, which increased with age, showed the lowest (proliferation index, 1.19 ± 0.09) (Supplemental Figure 2B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MG-132 treatment increased p53FL but did not increase Δ133p53 protein in whole CD8+ T lymphocytes or in CD28+CD57- and CD28-CD57+ populations.

    “Whereas treatment with MG-132 resulted in increased p53FL levels in the whole population of CD8 + T lymphocytes and the CD28 + CD57 -and CD28 -CD57 + populations, the same treatment did not increase Δ133p53 protein levels in any of these populations (Supplemental Figure 8, A and B)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The CD28-CD57+ subset had shortened telomeres and more SA-β-gal-positive cells than the CD28+CD57- subset.

    “As previously reported for replicatively senescent CD8 + T lymphocytes (23,26,27), the CD28 -CD57 + subset had shortened telomeres and showed an increase in cells positive for senescence-associated β-galactosidase (SA-β-gal) compared with the CD28 + CD57 -subset (Figure 1, B and C, and Supplemental Figure 3).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Monteiro, 1996, J Immunol. source

      Not checked in the free run.

    • cites [26] source

      Not checked in the free run.

    • cites [27] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Cells with Δ133p53 knockdown underwent proliferation arrest within 10 days and showed SA-β-gal activity, whereas control cells proliferated well.

    “The cells with Δ133p53 knockdown underwent proliferation arrest within 10 days of induction of SA-β-gal activity, whereas control cells were proliferating well (Figure 5, B and C, and Supplemental Figure 16A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A siRNA against Δ133p53 efficiently downregulated Δ133p53 expression without affecting p53FL.

    “A siRNA oligonucleotide against Δ133p53, which was transfected every 3-4 days by nucleofection, efficiently downregulated Δ133p53 expression with no effect on p53FL (Figure 5A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CD28 reconstitution restored Δ133p53 protein without changing Δ133p53 mRNA, p53FL, or CD57+ frequency.

    “Reconstitution of CD28 restored the expression of Δ133p53 protein without changes in Δ133p53 mRNA levels, p53FL levels, or CD57 + cell frequency (Figure 4B and Supplemental Figure 12, C-E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    p53FL was upregulated during in vitro culture, while p53β expression showed only a marginal increase or remained constant through week 8.

    “While p53FL was upregulated during in vitro culture, p53β expression showed only a marginal increase or remained constant through week 8 (Figure 3H and Supplemental Figure 10, D-F).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Δ133p53-rescued CD28- cells showed increased central memory markers CD27 and CD62L and decreased late-differentiated markers PD-1 and LAG-3.

    “In addition to the attenuation of senescence factors, these Δ133p53-rescued CD28 - cells also showed increased expression of central memory markers like CD27 and CD62L and decreased expression of late-differentiated markers like PD-1 and LAG-3 (Supplemental Figure 14, C-J).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Restoring Δ133p53 lengthened the replicative lifespan, and this coincided with renewed expression of CD28, CD27, and CD62L.

    “The extension of the replicative lifespan by Δ133p53 restoration was coincident with restored expression of CD28 along with CD27 and CD62L”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Under nutlin-3a treatment, CD28+ cell frequency decreased, attributed to decreased CD28 mRNA.

    “Under this condition, CD28 + cell frequency was decreased, which was attributed to decreased expression of CD28 mRNA (Supplemental Figure 15, B-D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tumor-associated CD28-CD57+ subsets showed elevated p53β and diminished Δ133p53 protein, increased HP1-γ foci, and elevated SASP factors IL6 and IL8.

    “The CD28 -CD57 + subsets, similar to those from blood CD8 + T lymphocytes, showed switching of p53 isoform abundance, i.e., elevated p53β and diminished Δ133p53 protein levels, and senescence phenotypes, including increased HP1-γ foci and elevated SASP factors, such as IL6 and IL8 (Figure 2, G-I, and Supplemental Figure 9, A-D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Δ133p53 knockdown decreased CD28 mRNA expression and CD28+ cell number, with no remarkable change in CD57+ cells.

    “Knockdown of Δ133p53 decreased CD28 mRNA expression and CD28 + cell number, with no remarkable change in CD57 + cells (Figure 5, D and E, and Supplemental Figure 16, B-D), again indicating that Δ133p53 positively regulates CD28 at the mRNA level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nutlin-3a treatment in control vector-transduced cells decreased CD28 mRNA by 60%, while Δ133p53 overexpression largely abrogated this repression (19% decrease).

    “While nutlin-3a treatment in control vectortransduced cells resulted in significant repression of CD28 mRNA (60% decrease), similar to that observed in untransduced cells, Δ133p53 overexpression largely abrogated the repressive effect of nutlin-3a on CD28 mRNA expression (19% decrease) (Supplemen-tal Figure 15, D and E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lentiviral overexpression of Flag-tagged p53β in the CD28+ population stopped proliferation after 10 days and increased SA-β-gal activity.

    “While vector control cells were proliferating well, the p53β-overexpressing cells stopped proliferating after 10 days, with an increase in SA-β-gal activity (Figure 5, G and H, and Supplemental Figure 17A), similar to the results using whole CD8 + T lymphocytes (Supplemental Figure 13).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Proliferation-arrested cultured cells showed increased SA-β-gal-positive cells and increased HP1-γ and γ-H2AX foci.

    “In these proliferation-arrested cells, an increase in SA-β-gal-posi- tive cells and increased numbers of HP1-γ and γ-H2AX foci were observed (Figure 3, B-E, and Supplemental Figure 10, A and B), similar to the senescent CD8 + T lymphocytes that accumulated in vivo (Figure 1, C-G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Δ133p53 expression in CD28- cells induced CD28 mRNA and converted up to 30% of cells to CD28+.

    “Upon Δ133p53 expression in CD28 -cells, CD28 mRNA expression was induced, and up to 30% of cells were converted to CD28 + (Figure 4, F-H), whereas CD57 expression was unaltered (Supplemental Figure 14, A and B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CD28- cells had unchanged Δ133p53 mRNA, increased p53β mRNA, and decreased SRSF3 mRNA compared with CD28+ cells.

    “Compared with CD28 + cells, CD28 -cells expressed decreased Δ133p53 protein and elevated p53β protein levels, again with unchanged Δ133p53 mRNA, increased p53β mRNA, decreased SRSF3 mRNA, and elevated IL6 and IL8 levels (Supplemental Figure 11, B-G), consistent with the results from CD28/CD57 quadrants (Figures 1 and 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Transduction of Δ133p53 into CD28- cells increased proliferation rate, bypassed the senescence point of vector controls, and continued for 4 or 5 more PDLs.

    “When CD28 -cells were transduced with a lentiviral construct for Δ133p53 expression (Figure 4D), the transduced cells showed higher proliferation rate, bypassed the senescence point of vector control cells, and continued to proliferate for 4 or 5 more PDLs (Figure 4E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In tumor CD28-CD57+ cells, elevated p53β protein coincided with increased p53β mRNA and decreased SRSF3 mRNA.

    “The elevated levels of p53β protein in the CD28 - CD57 + cells were again coincident with increased p53β mRNA and decreased SRSF3 mRNA (Figure 2, J and K, and Supplemental Figure 9, E and F).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Δ133p53 undergoes autophagic breakdown, whereas p53FL and p53β are broken down by the proteasome.

    “The autophagic degradation of Δ133p53 is in contrast to the proteasome-mediated degradation of p53FL and p53β (15)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In CD8+ T lymphocytes nearing senescence, restoring Δ133p53 postponed the onset of proliferation arrest, lengthened the replicative lifespan, and reversed senescence phenotypes to a degree comparable to CD28 reconstitution.

    “Δ133p53 delayed the onset of senescent proliferation arrest, extended the replicative lifespan, and rescued cells from senescence phenotypes as efficiently as the reconstitution of CD28.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In whole CD8+ T lymphocytes from 3 donors, nutlin-3a but not nutlin-3b activated p53FL, shown by increased p53FL protein, increased p53 phosphorylation at serine 15, and induced p21WAF1.

    “In whole CD8 + T lymphocytes from 3 donors, treatment with nutlin-3a (an inhibitor of MDM2), but not nutlin-3b (an inactive enantiomer), resulted in the activation of p53FL, evidenced by increased amounts of p53FL protein, increased p53 phosphorylation at the serine 15 residue, and induced expression of a p53 target, p21 WAF1 (Supplemental Figure 15A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In vitro culture led to loss of the CD57+ population, which contradicted the age-dependent increase in CD57+ population in vivo.

    “The frequency of the CD28 + population decreased gradually toward the end of the replicative lifespan (week 12; Figure 3F), reproducing its donor age-dependent decrease in vivo, although loss of CD57 + population during in vitro culture contradicted the age-dependent increase in CD57 + population in vivo (compare Supplemental Figure 1C and Supplemental Figure 10C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    p53β overexpression was associated with a significant increase in CD57+ cells but not CD28+ cells.

    “Overexpression of p53β was associated with a significant increase in CD57 + cells, but not CD28 + cells (Supplemental Figure 17, B-E), suggesting coregulation of p53β and CD57.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When cultured, blood CD8+ T lymphocytes become replicatively senescent, lose CD28, and downregulate Δ133p53.

    “Blood CD8 + T lymphocytes undergo replicative senescence in vitro, with loss of CD28 and downregulation of Δ133p53.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Knocking down Δ133p53 or overexpressing p53β triggers senescence in CD8+CD28+ T lymphocytes.

    “Δ133p53 knockdown or p53β overexpression induces cellular senescence in CD8 + CD28 + T lymphocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In vivo, CD28-CD57+ CD8+ T lymphocytes have lower Δ133p53 and higher p53β.

    “Diminished Δ133p53 and elevated p53β in the CD28 -CD57 + subset of CD8 + T lymphocytes in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In tumor-associated CD8+ T lymphocytes, Δ133p53 is lower and p53β is higher.

    “Quantitative data summary of Δ133p53 and p53β protein expression in the CD28 + CD57 -and CD28 -CD57 + subsets of tumor-associated CD8 + T lymphocytes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Restoring either CD28 or Δ133p53 in CD8+CD28- T lymphocytes lengthens their replicative lifespan.

    “Reconstitution of CD28 or Δ133p53 expression extends replicative lifespan in CD8 + CD28 -T lymphocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    With increasing donor age, the CD28+CD57- subset shrank while the CD28-CD57+ subset expanded.

    “CD28 + CD57 -subsets decreased and CD28 -CD57 + subsets increased with donor age.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Premalignant colon adenomas with pathologically induced senescent cells show elevated p53β and reduced Δ133p53, and loss of this pattern is linked to malignant progression.

    “Premalignant colon adenomas with pathologically induced senescent cells in vivo also showed a specific profile of p53 isoform expression (i.e., elevated levels of p53β and reduced levels of Δ133p53), the loss of which was associated with malignant progression to colon carcinomas (15).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Late-differentiated CD8+ T lymphocytes are marked by CD28 loss, CD57 gain, and shortened telomeres, and they contribute to immunosenescence.

    “These cells are characterized by loss of CD28 (a costimulatory receptor; ref. 20) and gain of CD57 (also known as human natural killer-1; ref. 22), as well as shortened telomeres (23), and directly contribute to immunosenescence (20,24).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites ref. 20

      Not checked in the free run.

    • cites ref. 22

      Not checked in the free run.

    • cites [23] Monteiro, 1996, J Immunol. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Cellular senescence is a stable halt in cell division caused by telomere shortening or by stresses such as oncogene activation.

    “Cellular senescence is sustained cell proliferation arrest induced either by telomere attrition (replicative senescence; refs.1,2) or by cellular stresses such as oncogene activation (stress-induced premature senescence; ref. 3).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites refs.1,2

      Not checked in the free run.

    • cites ref. 3

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD8+ T lymphocytes are easy to isolate and analyze ex vivo and can be genetically modified in vitro, making them a useful model for studying cellular senescence in vivo.

    “CD8 + T lymphocytes, which can be easily isolated and analyzed ex vivo via flow cytometry or other antibody-based methods and can be genetically modified in vitro (17), provide a useful cell model to study cellular senescence in vivo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    CD8+ T lymphocytes with these late-differentiated characteristics can impair tumor-specific T cell immunity.

    “CD8 + T lymphocytes with these characteristics can also be a cause of functional impairment of tumor-specific T cell immunity (25).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p53β is a C-terminally truncated isoform that works with full-length p53, whereas Δ133p53 is an N-terminally truncated isoform that dominantly inhibits full-length p53.

    “Among them are p53β, a C-terminally truncated isoform that cooperates with p53FL, and Δ133p53, an N-terminally truncated isoform that inhibits p53FL in a dominant-negative manner (14).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In cultured normal human fibroblasts, p53β speeds up and Δ133p53 suppresses replicative senescence.

    “In normal human fibroblasts cultured in vitro, p53β accelerates and Δ133p53 represses replicative senescence (15), consistent with their modes of functional interaction with p53FL.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Human TP53 produces at least 13 natural isoforms through alternative splicing and alternative promoter use.

    “The human TP53 gene encodes, in addition to full-length p53 protein (p53FL), at least 13 natural isoforms due to alternative splicing and usage of alternative promoters (13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    CD28 signaling is connected to higher Δ133p53 protein, because NF-κB and its downstream mTOR activation may suppress autophagy.

    “This finding links CD28 function to Δ133p53 upregulation at the protein level, since NF-κB and its activation of mTOR, a major downstream pathway activated by the CD28 signaling, may repress autophagy (36)(37)(38)(39)(40).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [36] source

      Not checked in the free run.

    • cites [37] source

      Not checked in the free run.

    • cites [38] Ward, 1996, Biochem J. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Fluorescence data were acquired from at least 10,000 cells.

    “Fluorescence data from at least 10,000 cells were acquired using FACSDiva software in LSRII (BD Biosciences).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Successive in vitro culture of isolated blood CD8+ T lymphocytes resulted in senescent proliferation arrest with CD28 loss and Δ133p53 downregulation, consistent with in vivo aging.

    “Successive in vitro culture of isolated CD8 + T lymphocytes from blood resulted in senescent proliferation arrest with CD28 loss and Δ133p53 downregulation, consistent with their regulation during in vivo aging, enabling in vitro functional analyses of the costimu-latory receptor and the p53 isoforms.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    The purity of each sorted population was checked and only populations >90% pure were used in all experiments.

    “The purity of each population was checked and >90% pure cells were used for all experiments.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Immunoblot results were confirmed using a full blot probed with the Δ133p53-specific antibody MAP4 or the antibody CM1.

    “These results were confirmed by immunoblot analysis using a full blot, which was probed with the Δ133p53-specific antibody MAP4 or the antibody CM1 (31), which recognizes p53FL, Δ133p53, p53β, and other p53 isoforms (Supplemental Figure 6, B and C).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Marcel, 2013, Methods Mol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    p53β overexpression drives cells toward senescence, with expression of senescence-associated factors and terminally differentiated markers PD-1 and LAG-3.

    “These findings suggest that p53β overexpression leads cells toward senescence, with expression of senescence-associated factors as well as terminally differentiated markers such as PD-1 and LAG-3.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Blood samples from healthy donors were obtained with informed consent under NIH IRB approval.

    “Human peripheral blood samples were collected from healthy donors after informed consent and in accordance with the NIH IRB (study no.99-CC-0168).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Tumor-associated CD8+ T lymphocytes and tumor cells probably interact within the tumor microenvironment.

    “In addition, cross-talk between these T lymphocytes and tumor cells likely exists in the tumor microenvironment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Senescent CD8+ T lymphocytes aid tumor immune evasion by being functionally unresponsive and by suppressing responder T cells.

    “Senescent CD8 + T lymphocytes not only contribute to tumor immune evasion through their functional unresponsiveness (42) and their suppressor function toward responder T cells (41,43)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] source

      Not checked in the free run.

    • cites [41] source

      Not checked in the free run.

    • cites [43] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These p53 isoforms control tumorigenesis in vivo through both tumor-cell-intrinsic and tumor-cell-extrinsic effects.

    “suggests that these p53 isoforms regulate tumorigenesis in vivo in both tumor cellautonomous and non-autonomous manners.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Lung tumor specimens were acquired via the CINJ Biospecimen Repository Services with UMDNJ IRB approval.

    “Lung tumors were obtained through the CINJ Biospecimen Repository Services under UMDNJ IRB approval (study no.0220100267).”
    Quote in the paperNot a substantial claim
53 of 53

  • The authors state this as an assumption.

    Senescent cells actively contribute to aging phenotypes.

    “Senescent cells accumulate in vivo during aging and are assumed to contribute actively to aging phenotypes (4-6).”

  • The paper relies on this without support.

    Δ133p53 is naturally expressed at high levels in normal proliferative cells.

    “Since Δ133p53 is a natural isoform of p53 and is physiologically expressed in normal proliferative cells at high levels, enhanced expression of Δ133p53 may lead to a safe method for functional restoration of CD8 + T lymphocytes with minimum concern for malignant transformation.”
2 of 2

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?

  • Senescent T cells exhibit downregulation of CD27 and CD28 and upregulation of CD57, KLRG-1, Tim-3, TIGIT, and CTLA-4.

    “Senescent T cells exhibit abnormal phenotypes, including downregulation of CD27, CD28, and upregulation of CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, and cytotoxic T-lymphocyte-associated protein 4, which are tightly related to malignant tumors.”

    From Immunosenescence: a key player in cancer development (2020) · cites this paper as [42]

  • With the loss of CD27 and CD28, there is an increase in the expression of P16 and P21.

    “Moreover, with the loss of CD27 and CD28, there is an increase in the expression of P16 and P21, which are involved in cell cycle regulation [42] (Fig. 2).”

    From Immunosenescence: a key player in cancer development (2020) · cites this paper as [42]

The citation lists haven’t been fetched yet

References 60 · Cited by 164

Research works printed but not linked: 41

  1. 10.1016/0014-4827(65)90211-9 · DOI · Paper page
  2. 10.1016/0531-5565(92)90068-B · DOI
  3. 10.1038/nature05268 · DOI · Paper page
  4. 10.1172/JCI68833 · DOI
  5. 10.1172/JCI64098 · DOI · Paper page
  6. Beltrami, 2012, Clin Pharmacol., 91, 21
  7. 10.1146/annurev-pathol-121808-102144 · DOI · Paper page
  8. 10.1038/nature10599 · DOI · Paper page
  9. 10.1016/j.cell.2007.07.003 · DOI · Paper page
  10. 10.1101/cshperspect.a000927 · DOI · Paper page
  11. 10.1007/s10875-010-9449-7 · DOI · Paper page
  12. 10.1146/annurev-med-042909-093756 · DOI · Paper page
  13. 10.1016/S0047-6374(00)00199-8 · DOI
  14. 10.1182/blood-2002-07-2103 · DOI · Paper page
  15. 10.1016/j.coi.2009.05.023 · DOI · Paper page
  16. 10.1038/436642a · DOI · Paper page
  17. 10.1038/ncb1095 · DOI · Paper page
  18. Marcel, 2013, Methods Mol., 962, 15, 10.1007/978-1-62703-236-0_2 · DOI · Paper page
  19. 10.1038/nbt0898-743 · DOI
  20. 10.1111/j.1474-9726.2008.00448.x · DOI
  21. 10.1101/cshperspect.a002436 · DOI · Paper page
  22. 10.1111/j.1600-065X.2011.01011.x · DOI · Paper page
  23. Ward, 1996, Biochem J., 318, 361, 10.1042/bj3180361 · DOI · Paper page
  24. 10.1074/jbc.M602097200 · DOI
  25. 10.1038/ncb2708 · DOI
  26. 10.1016/j.virol.2004.11.028 · DOI · Paper page
  27. 10.2174/1570162033485348 · DOI
  28. 10.1097/00002030-200005050-00002 · DOI
  29. 10.1158/1078-0432.CCR-12-1362 · DOI
  30. 10.1056/NEJMoa1200690 · DOI · Paper page
  31. 10.1016/j.stem.2012.12.006 · DOI
  32. 10.1038/nrc3322 · DOI
  33. 10.1038/ng.428 · DOI
  34. 10.1016/j.cell.2011.05.036 · DOI
  35. 10.1016/j.stem.2012.11.002 · DOI
  36. 10.1073/pnas.0909390107 · DOI
  37. 10.1016/0531-5565(89)90009-0 · DOI
  38. 10.1097/CJI.0b013e3181e311cb · DOI
  39. 10.1016/S0047-6374(03)00012-5 · DOI
  40. 10.1073/pnas.0609367104 · DOI
  41. 10.2307/2136404 · DOI · Paper page

Authors
Mondal, A. M., Horikawa, I., Pine, S. R., Fujita, K., Morgan, K. M., Vera, E., Mazur, S. J., Appella, E., Vojtesek, B., Blasco, M. A., Lane, D. P., & Harris, C. C.
Affiliations
  • National Institutes of Health (US)
  • Spanish National Cancer Research Centre (ES)
  • Agency for Science, Technology and Research (SG)
Corresponding author
Harris, Curtis C.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2013-11-15
Volume
123
Issue
12
Pages
5247-5257
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci70355
PMC
PMC3859419
OpenAlex
W2026610143
Semantic Scholar
91e57ae5d0de3c59d81b090f77fa01d447b43cdd
Cited by
164
References
60
Citations by year
2026: 11 · 2025: 16 · 2024: 25 · 2023: 11 · 2022: 11 · 2021: 21 · 2020: 15 · 2019: 9 · 2018: 12 · 2017: 10 · 2016: 10 · 2015: 7 · 2014: 6
FWCI
5.33
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Rutgers Cancer Institute of New Jersey (P30 CA072720)
  • Grantová Agentura České Republiky (GAP301/11/1678, CZ.1.05/2.1.00/03.0101, P206/12/G151.)
  • National Institutes of Health
  • National Cancer Institute (K22CA140719, P30CA072720)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
p53 isoforms, Δ133p53, replicative senescence, cellular senescence, T cells, CD8+ T cells, immunosenescence, CD28, aging, lung cancer, cell proliferation, replicative lifespan, senolytics
MeSH terms
Adult, Aged, Autophagy, Cell Division, Cells, Cultured, Female, Humans, Leupeptins, Lung Neoplasms, Male, Middle Aged, Neoplasm Proteins, Recombinant Proteins, Transduction, Genetic, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Lymphocytes, Tumor-Infiltrating, Cellular Senescence, CD8-Positive T-Lymphocytes, Macrolides, Protein Isoforms, Young Adult, Tumor Microenvironment, Proteolysis

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review