An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells
Open accessAbstract
Memory CD8(+) T cells are critical for long-term immunity, but the genetic pathways governing their formation remain poorly defined. This study shows that the IL-10-IL-21-STAT3 pathway is critical for memory CD8(+) T cell development after acute LCMV infection. In the absence of either interleukin-10 (IL-10) and IL-21 or STAT3, virus-specific CD8(+) T cells retain terminal effector (TE) differentiation states and fail to mature into protective memory T cells that contain self-renewing central memory T cells. Expression of Eomes, BCL-6, Blimp-1, and SOCS3 was considerably reduced in STAT3-deficient memory CD8(+) T cells, and BCL-6- or SOCS3-deficient CD8(+) T cells also had perturbed memory cell development. Reduced SOCS3 expression rendered STAT3-deficient CD8(+) T cells hyperresponsive to IL-12, suggesting that the STAT3-SOCS3 pathway helps to insulate memory precursor cells from inflammatory cytokines that drive TE differentiation. Thus, memory CD8(+) T cell precursor maturation is an active process dependent on IL-10-IL-21-STAT3 signaling.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
IL-10- and IL-21-mediated STAT3 activation helps generate stable, long-lived memory CD8+ T cells through regulating Eomes, BCL6, and Blimp1.
“IL-10– and IL-21–mediated STAT3 activation”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Cui et al., 2011
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Joshi, N. S., Cui, W., Chandele, A., Lee, H. K., Urso, D. R., Hagman, J., Gapin, L., & Kaech, S. M. (2007) · Immunity · doi:10.1016/j.immuni.2007.07.010 · Cited by 1,861 · see citing works
Self-citationKaech, S. M., Tan, J. T., Wherry, E. J., Konieczny, B. T., Surh, C. D., & Ahmed, R. (2003) · Nature Immunology · doi:10.1038/ni1009 · Cited by 1,830 · cited 4× · see citing works
“Class I MHC tetramers were generated as described previously (Kaech et al., 2003).”
InfluentialSelf-citationWelte, T., Zhang, S. S. M., Wang, T., Zhang, Z., Hesslein, D. G. T., Yin, Z., Kano, A., Iwamoto, Y., Li, E., Craft, J. E., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0237137100 · Cited by 381 · see citing works
Self-citationGenomic views of STAT function in CD4+ T helper cell differentiation
O'Shea, J. J., Lahesmaa, R., Vahedi, G., Laurence, A., & Kanno, Y. (2011) · Nature Reviews Immunology · doi:10.1038/nri2958 · Cited by 295 · see citing works
Flagged first, then by citations
Research works printed but not linked: 50
- Agarwal P Raghavan A Nandiwada SL Curtsinger JM Bohjanen PR Mueller DL Mescher MF 2009 Gene regulation and chromatin remodeling by IL-12 and type I IFN in programming for CD8 T cell effector function and memory J Immunol 183 1695 1704 19592655 PMC2893405
- Araki K Turner AP Shaffer VO Gangappa S Keller SA Bachmann MF Larsen CP Ahmed R 2009 mTOR regulates memory CD8 T-cell differentiation Nature 460 108 112 19543266 PMC2710807
- Badovinac VP Messingham KA Jabbari A Haring JS Harty JT 2005 Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination Nature medicine 11 748 756 15951824
- Badovinac VP Porter BB Harty JT 2004 CD8+ T cell contraction is controlled by early inflammation Nature immunology 5 809 817 15247915
- Banerjee A Gordon SM Intlekofer AM Paley MA Mooney EC Lindsten T Wherry EJ Reiner SL 2010 Cutting edge: The transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche J Immunol 185 4988 4992 20935204 PMC2975552
- Barker BR Gladstone MN Gillard GO Panas MW Letvin NL 2010 Critical role for IL-21 in both primary and memory anti-viral CD8+ T-cell responses European journal of immunology 40 3085 3096 21061439 PMC3119210
- Biswas PS Pedicord V Ploss A Menet E Leiner I Pamer EG 2007 Pathogen-specific CD8 T cell responses are directly inhibited by IL-10 J Immunol 179 4520 4528 17878348
- Brooks DG Walsh KB Elsaesser H Oldstone MB 2010 IL-10 directly suppresses CD4 but not CD8 T cell effector and memory responses following acute viral infection Proceedings of the National Academy of Sciences of the United States of America 107 3018 3023 20133700 PMC2840337
- Calame K 2008 Activation-dependent induction of Blimp-1 Current opinion in immunology 20 259 264 18554885
- Castellino F Germain RN 2007 Chemokine-guided CD4+ T cell help enhances generation of IL-6RalphahighIL-7Ralpha high prememory CD8+ T cells J Immunol 178 778 787 17202339
- Chaudhry A Rudra D Treuting P Samstein RM Liang Y Kas A Rudensky AY 2009 CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner Science (New York, NY) 326 986 991 PMC4408196 19797626
- Cui W Joshi NS Jiang A Kaech SM 2009 Effects of Signal 3 during CD8 T cell priming: Bystander production of IL-12 enhances effector T cell expansion but promotes terminal differentiation Vaccine 27 2177 2187 19201385 PMC2803112
- Cui W Kaech SM 2010 Generation of effector CD8+ T cells and their conversion to memory T cells Immunological reviews 236 151 166 20636815 PMC4380273
- Diehl SA Schmidlin H Nagasawa M van Haren SD Kwakkenbos MJ Yasuda E Beaumont T Scheeren FA Spits H 2008 STAT3-mediated up-regulation of BLIMP1 Is coordinated with BCL6 down-regulation to control human plasma cell differentiation J Immunol 180 4805 4815 18354204 PMC2396731
- Egwuagu CE Yu CR Zhang M Mahdi RM Kim SJ Gery I 2002 Suppressors of cytokine signaling proteins are differentially expressed in Th1 and Th2 cells: implications for Th cell lineage commitment and maintenance J Immunol 168 3181 3187 11907070
- Foulds KE Rotte MJ Seder RA 2006 IL-10 is required for optimal CD8 T cell memory following Listeria monocytogenes infection J Immunol 177 2565 2574 16888018
- Hinrichs CS Spolski R Paulos CM Gattinoni L Kerstann KW Palmer DC Klebanoff CA Rosenberg SA Leonard WJ Restifo NP 2008 IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy Blood 111 5326 5333 18276844 PMC2396726
- Ichii H Sakamoto A Arima M Hatano M Kuroda Y Tokuhisa T 2007 Bcl6 is essential for the generation of long-term memory CD4+ T cells International immunology 19 427 433 17307796
- Ichii H Sakamoto A Kuroda Y Tokuhisa T 2004 Bcl6 acts as an amplifier for the generation and proliferative capacity of central memory CD8+ T cells J Immunol 173 883 891 15240675
- Intlekofer AM Banerjee A Takemoto N Gordon SM Dejong CS Shin H Hunter CA Wherry EJ Lindsten T Reiner SL 2008 Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin Science (New York, NY) 321 408 411 PMC2807624 18635804
- Intlekofer AM Takemoto N Kao C Banerjee A Schambach F Northrop JK Shen H Wherry EJ Reiner SL 2007 Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells The Journal of experimental medicine 204 2015 2021 17698591 PMC2118697
- Intlekofer AM Takemoto N Wherry EJ Longworth SA Northrup JT Palanivel VR Mullen AC Gasink CR Kaech SM Miller JD 2005 Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin Nature immunology 6 1236 1244 16273099
- Jacob J Baltimore D 1999 Modelling T-cell memory by genetic marking of memory T cells in vivo Nature 399 593 597 10376601
- Kaech SM Hemby S Kersh E Ahmed R 2002 Molecular and functional profiling of memory CD8 T cell differentiation Cell 111 837 851 12526810
- Kaech SM Wherry EJ 2007 Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection Immunity 27 393 405 17892848 PMC3431921
- Kalia V Sarkar S Subramaniam S Haining WN Smith KA Ahmed R 2010 Prolonged interleukin-2Ralpha expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo Immunity 32 91 103 20096608
- Kallies A Xin A Belz GT Nutt SL 2009 Blimp-1 transcription factor is required for the differentiation of effector CD8(+) T cells and memory responses Immunity 31 283 295 19664942
- Kolumam GA Thomas S Thompson LJ Sprent J Murali-Krishna K 2005 Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection The Journal of experimental medicine 202 637 650 16129706 PMC2212878
- Liu N Phillips T Zhang M Wang Y Opferman JT Shah R Ashton-Rickardt PG 2004 Serine protease inhibitor 2A is a protective factor for memory T cell development Nature immunology 5 919 926 15311278
- Maris CH Chappell CP Jacob J 2007 Interleukin-10 plays an early role in generating virus-specific T cell anergy BMC immunology 8 8 17570849 PMC1903364
- Matsuda T Nakamura T Nakao K Arai T Katsuki M Heike T Yokota T 1999 STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells The EMBO journal 18 4261 4269 10428964 PMC1171502
- Nguyen KB Watford WT Salomon R Hofmann SR Pien GC Morinobu A Gadina M O’Shea JJ Biron CA 2002 Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection Science (New York, NY) 297 2063 2066 12242445
- Novy P Huang X Leonard WJ Yang Y 2011 Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection J Immunol 186 2729 2738 21257966 PMC3059504
- Ozaki K Spolski R Ettinger R Kim HP Wang G Qi CF Hwu P Shaffer DJ Akilesh S Roopenian DC 2004 Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6 J Immunol 173 5361 5371 15494482
- Palmer DC Restifo NP 2009 Suppressors of cytokine signaling (SOCS) in T cell differentiation, maturation, and function Trends in immunology 30 592 602 19879803 PMC2787651
- Pearce EL Walsh MC Cejas PJ Harms GM Shen H Wang LS Jones RG Choi Y 2009 Enhancing CD8 T-cell memory by modulating fatty acid metabolism Nature 460 103 107 19494812 PMC2803086
- Pipkin ME Sacks JA Cruz-Guilloty F Lichtenheld MG Bevan MJ Rao A 2010 Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells Immunity 32 79 90 20096607 PMC2906224
- Rutishauser RL Martins GA Kalachikov S Chandele A Parish IA Meffre E Jacob J Calame K Kaech SM 2009 Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties Immunity 31 296 308 19664941 PMC2783637
- Sallusto F Lanzavecchia A Araki K Ahmed R 2011 From vaccines to memory and back Immunity 33 451 463 21029957 PMC3760154
- Sarkar S Kalia V Haining WN Konieczny BT Subramaniam S Ahmed R 2008 Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates The Journal of experimental medicine 205 625 640 18316415 PMC2275385
- Shuai K Liu B 2003 Regulation of JAK-STAT signalling in the immune system Nature reviews 3 900 911 14668806
- Spolski R Leonard WJ 2008a Interleukin-21: basic biology and implications for cancer and autoimmunity Annual review of immunology 26 57 79 17953510
- Spolski R Leonard WJ 2008b The Yin and Yang of interleukin-21 in allergy, autoimmunity and cancer Current opinion in immunology 20 295 301 18554883 PMC2546604
- Stritesky GL Muthukrishnan R Sehra S Goswami R Pham D Travers J Nguyen ET Levy DE Kaplan MH 2011 The transcription factor STAT3 is required for T helper 2 cell development Immunity 34 39 49 21215659 PMC3040244
- Sun JC Williams MA Bevan MJ 2004 CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection Nature immunology 5 927 933 15300249 PMC2776074
- Tripathi P Kurtulus S Wojciechowski S Sholl A Hoebe K Morris SC Finkelman FD Grimes HL Hildeman DA 2010 STAT5 is critical to maintain effector CD8+ T cell responses J Immunol 185 2116 2124 20644163 PMC2991082
- Yang XO Panopoulos AD Nurieva R Chang SH Wang D Watowich SS Dong C 2007 STAT3 regulates cytokine-mediated generation of inflammatory helper T cells The Journal of biological chemistry 282 9358 9363 17277312
- Yi JS Ingram JT Zajac AJ 2010 IL-21 deficiency influences CD8 T cell quality and recall responses following an acute viral infection J Immunol 185 4835 4845 20844201 PMC2950881
- Yoshimura A Naka T Kubo M 2007 SOCS proteins, cytokine signalling and immune regulation Nature reviews 7 454 465 17525754
- Zhou X Yu S Zhao DM Harty JT Badovinac VP Xue HH 2010 Differentiation and persistence of memory CD8(+) T cells depend on T cell factor 1 Immunity 33 229 240 20727791 PMC2928475
Cited by
Sorted by citations
T follicular helper cell differentiation, function, and roles in disease
Crotty, S. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.004 · Cited by 1,847 · see citing works
Transcriptional control of effector and memory CD8+ T cell differentiation
Kaech, S. M., & Cui, W. (2012) · Nature Reviews Immunology · doi:10.1038/nri3307 · Cited by 1,628 · see citing works
Self-citationMechanisms and consequences of Jak–STAT signaling in the immune system
Villarino, A. V., Kanno, Y., & O'Shea, J. J. (2017) · Nature Immunology · doi:10.1038/ni.3691 · Cited by 1,221 · see citing works
The multifaceted role of CD4+ T cells in CD8+ T cell memory
Laidlaw, B. J., Craft, J. E., & Kaech, S. M. (2016) · Nature Reviews Immunology · doi:10.1038/nri.2015.10 · Cited by 657 · see citing works
Self-citationSOCS3, a Major Regulator of Infection and Inflammation
Carow, B., & Rottenberg, M. E. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00058 · Cited by 555 · see citing works
Metabolic switching and fuel choice during T‐cell differentiation and memory development
van der Windt, G. J. W., & Pearce, E. L. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01150.x · Cited by 563 · see citing works
Heterogeneity in the Differentiation and Function of CD8+ T Cells
Mittrücker, H.-W., Visekruna, A., & Huber, M. (2014) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-014-0293-y · Cited by 325 · see citing works
IL-10: Master Switch from Tumor-Promoting Inflammation to Antitumor Immunity
Oft, M. (2014) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-13-0214 · Cited by 322 · see citing works
Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“IL-10– and IL-21–mediated STAT3 activation (Cui et al., 2011) helps generate stable, long-lived memory cells (Cui et al.”
BackgroundGraef, P., Buchholz, V. R., Stemberger, C., Flossdorf, M., Henkel, L., Schiemann, M., Drexler, I., Höfer, T., Riddell, S. R., & Busch, D. H. (2014) · Immunity · doi:10.1016/j.immuni.2014.05.018 · Cited by 311 · see citing works
T cell factor 1: A master regulator of the T cell response in disease
Escobar, G., Mangani, D., & Anderson, A. C. (2020) · Science Immunology · doi:10.1126/sciimmunol.abb9726 · Cited by 211 · see citing works
Leonard, W. J., & Wan, C.-K. (2016) · F1000Research · doi:10.12688/f1000research.7634.1 · Cited by 184 · see citing works
Intersection of mTOR and STAT signaling in immunity
Saleiro, D., & Platanias, L. C. (2015) · Trends in Immunology · doi:10.1016/j.it.2014.10.006 · Cited by 142 · see citing works
Lee, K., Shin, K., Kim, G., Song, Y. C., Bae, E., Kim, I., Koh, C., & Kang, C. (2016) · Aging Cell · doi:10.1111/acel.12435 · Cited by 125 · see citing works
Mumm, J. B., & Oft, M. (2013) · BioEssays · doi:10.1002/bies.201300004 · Cited by 53 · see citing works
Kim, E., Cheng, Y., Bolton-Gillespie, E., Cai, X., Ma, C., Tarangelo, A., Le, L., Jambhekar, M., Raman, P., Hayer, K. E., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20160719 · Cited by 18 · see citing works
- Authors
- Cui, W., Liu, Y., Weinstein, J. S., Craft, J., & Kaech, S. M.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Kaech, Susan M.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 35
- Issue
- 5
- Pages
- 792-805
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC3431922
- OpenAlex
- W1973601490
- Cited by
- 410
- References
- 4
- Citations by year
- 2026: 21 · 2025: 21 · 2024: 20 · 2023: 18 · 2022: 31 · 2021: 32 · 2020: 20 · 2019: 28 · 2018: 26 · 2017: 28 · 2016: 31 · 2015: 34 · 2014: 38 · 2013: 37 · 2012: 23
- FWCI
- 14.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Allergy and Infectious Diseases (AI075157, R01AI075157, R21AI081150, R01AI074699, R01AI066232)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR40072, R01AR040072, AR-44076, R01AR044076)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- memory CD8+ T cells, IL-10, IL-21, STAT3, SOCS3, BCL6, Blimp-1, Eomes, central memory T cells, LCMV infection, T cell differentiation, IL-12 signaling, memory precursor cells
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Positive Regulatory Domain I-Binding Factor 1, Interleukin-21, Animals, Cell Differentiation, Immunologic Memory, Interleukins, Transcription Factors, Signal Transduction, Interleukin-10, Mice, Knockout, CD8-Positive T-Lymphocytes, Gene Expression Regulation, Developmental, T-Box Domain Proteins, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice, Proto-Oncogene Proteins c-bcl-6
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.
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
