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Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells
Abstract
A major unanswered question is what distinguishes the majority of activated CD8 T cells that die after an acute viral infection from the small fraction (5-10%) that survive to become long-lived memory cells. In this study we show that increased expression of the interleukin 7 receptor alpha-chain (IL-7Ralpha) identifies the effector CD8 T cells that will differentiate into memory cells. IL-7R(hi) effector cells contained increased amounts of antiapoptotic molecules, and adoptive transfer of IL-7R(hi) and IL-7R(lo) effector cells showed that IL-7R(hi) cells preferentially gave rise to memory cells that could persist and confer protective immunity. Thus, selective expression of IL-7R identifies memory cell precursors, and this marker may be useful in predicting the number of memory T cells generated after infection or immunization.
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“Ag-specific CD8 T cells derived from the effector phase of a response can express various combinations of CD127 and KLRG1, which define either more short-lived effector cells (SLECs; CD127−KLRG1+), which are lost during the contraction phase of the immune response, or memory precursor effector cells (MPECs; CD127+KLRG1−), which are more likely to persist and contribute to memory populations [224,”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [224]
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“This population of CD127Hi effector CD8 T cells, which constitutes 5 to 10% of the effector pool, preferentially survives and differentiates from effector CD8 T cells with an activated phenotype, high levels of granzyme B, and low levels of Bcl-2 into memory CD8 T cells characterized by a resting phenotype, low granzy…”
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“In an attempt to provide the basis for this functional heterogeneity, we showed that the majority of PD1CD8 TILs lacked expression of CD127, and this phenotype is known to be associated with impaired effector-to-memory transition (20).”
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Chang, J. T., Palanivel, V., Kinjyo, I., Schambach, F., Intlekofer, A. M., Banerjee, A., Longworth, S. A., Vinup, K. E., Mrass, P., Oliaro, J., et al. (2007) · Science · doi:10.1126/science.1139393 · Cited by 845
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“CD69 memory T cells in lymphoid and mucosal sites were largely IL-7R (Figure 4B), indicative of a resting memory T cell phenotype, as IL-7R is downregulated on activated effector T cells (Dooms et al., 2007; Kaech et al., 2003; Paiardini et al., 2005; Seddiki et al., 2006).”
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Self-citationTCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision
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“After clearance of an acute viral infection, memory precursor cells present in the heterogeneous pool of effector CD8+ T cells will differentiate into long-lived memory cells in the absence of antigen(Joshi et al., 2007; Kaech et al., 2003; Sarkar et al., 2008).”
BackgroundSelf-citationHypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen
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“In mice the precursors of memory CD8 T cells could be identified as IL-7R hi cells, while the more abundant KLRG1 hi cells were shown to represent short lived effector cells (Joshi et al., 2007; Kaech et al., 2003; Kaech and Wherry, 2007; Sarkar et al., 2008).”
Self-citationFunctional and genomic profiling of effector CD8 T cell subsets with distinct memory fates
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Self-citationIL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors
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“, 1997), CD127 (Kaech et al., 2003), KLRG1, CD43 (1B11) (Hikono et al.”
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“This idea would be consistent with the recent demonstration that only the cells that re-express IL-7 receptor following a response to LCMV infection are competent to become memory cells (65).”
ResultKalia, V., Sarkar, S., Subramaniam, S., Haining, W. N., Smith, K. A., & Ahmed, R. (2010) · Immunity · doi:10.1016/j.immuni.2009.11.010 · Cited by 607
“Consistent with previous observations in the field, this early analysis of MP and TE subsets confirms that superior IL-2 production is a unique property of MP cells at different times of differentiation (Joshi et al., 2007; Kaech et al., 2003; Marzo et al., 2005; Sarkar et al., 2008; Wherry et al., 2003).”
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“In contrast, cells expressing higher levels of CD57 and KLRG1 and reduced levels of IL-7R, CD28, and CD27 were found to be senescent, having reduced telomere length, proliferative capacity, and survival (termed short-lived effector T [Tsle] cells) (Kaech et al., 2003; Rutishauser and Kaech, 2010).”
BackgroundMetabolic switching and fuel choice during T‐cell differentiation and memory development
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“Accordingly, it has been shown that cells generated during the peak of infection that have not terminally differentiated, express IL-7R and persist as long-lived memory T cells (123).”
BackgroundThe many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance
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“(48) demonstrated that expression of IL-7R on a small numbers of CD8 effector cells identifies that subset which is destined to differentiate into true memory cells, and we have demonstrated that IL-7 therapy augments the size of the CD8 memory pool generated following immunization (44).”
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“for the cytokine interleukin (IL)-7, CD127, representing about 10%of effector cells at the peak of the response, give rise to functional memory cells (Kaech et al. 2003).”
BackgroundSelf-citationGuidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)
Cossarizza, A., Chang, H., Radbruch, A., Abrignani, S., Addo, R., Akdis, M., Andrä, I., Andreata, F., Annunziato, F., Arranz, E., et al. (2021) · European Journal of Immunology · doi:10.1002/eji.202170126 · Cited by 531
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“It seems that naive cells are poised to respond to TSLP activation, whereas IL-7 seems to play a greater role that is related to their differentiation into memory cells (18).”
BackgroundAntigen-independent memory CD8 T cells do not develop during chronic viral infection
Wherry, E. J., Barber, D. L., Kaech, S. M., Blattman, J. N., & Ahmed, R. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407192101 · Cited by 495
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“IL-7 is required for maintenance of memory CD8 T cells (26, 36), and the alpha chain of its receptor, CD127, is downregulated on antigen-specific T cells in persistent LCMV and gammaherpesvirus infections (18, 27, 32, 48).”
BackgroundSelf-citationHuster, K. M., Busch, V., Schiemann, M., Linkemann, K., Kerksiek, K. M., Wagner, H., & Busch, D. H. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308054101 · Cited by 474
Effector CD8 T cells dedifferentiate into long-lived memory cells
Youngblood, B., Hale, J. S., Kissick, H. T., Ahn, E., Xu, X., Wieland, A., Araki, K., West, E. E., Ghoneim, H. E., Fan, Y., et al. (2017) · Nature · doi:10.1038/nature25144 · Cited by 481
Self-citationRole of PD-1 during effector CD8 T cell differentiation
Ahn, E., Araki, K., Hashimoto, M., Li, W., Riley, J. L., Cheung, J., Sharpe, A. H., Freeman, G. J., Irving, B. A., & Ahmed, R. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1718217115 · Cited by 486
“Next, we examined whether PD-1 blockade during acute infection has any effect on memory CD8 T cell formation and if this blockade modulates differentiation of the terminal effector (TE) and memory precursor (MP) CD8 T cell subsets (4).”
BackgroundSelf-citationSportès, C., Hakim, F. T., Memon, S. A., Zhang, H., Chua, K., Brown, M. R., Fleisher, T. A., Krumlauf, M., Babb, R. R., Chow, C. K., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20071681 · Cited by 476
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“The homeostatic expansion of memory CD8+ T cells does not rely solely on IL-7, however, these cells do constitutively express high levels of both IL-7Rα (CD127) and the components of the IL-15–IL-2 heterodimeric complex, IL-2– IL-15Rβ(CD122) and γc (CD132), and thus might be sensitive to IL-7 [30,38,42].”
BackgroundCD8+ T cells in the cancer-immunity cycle
Giles, J. R., Globig, A.-M., Kaech, S. M., & Wherry, E. J. (2023) · Immunity · doi:10.1016/j.immuni.2023.09.005 · Cited by 491
Self-citationUnderstanding the generation and function of memory T cell subsets
Lanzavecchia, A., & Sallusto, F. (2005) · Current Opinion in Immunology · doi:10.1016/j.coi.2005.04.010 · Cited by 460
Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity
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“These parameters showed that CD8 + DCs from T H cell–deficient (MHC class II–deficient) mice were marginally compromised in their ability to stimulate CD8 + T cell proliferation over the course of this short-term assay and notably deficient at inducing upregulation of Bcl-2, IL-2 receptor and IL-7 receptor; the latter…”
BackgroundMartin, M. D., & Badovinac, V. P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02692 · Cited by 464
“Interleukin 7 is required for the survival of naïve cells and promotes the survival of memory CD8T cells (64), and initial reports suggested that the expression of CD127, the alpha chain of the IL-7 receptor, could be used to identify memory precursor effector cells (MPECs) that display increased ability to form long-…”
Migration, maintenance and recall of memory T cells in peripheral tissues
Woodland, D. L., & Kohlmeier, J. E. (2009) · Nature reviews. Immunology · doi:10.1038/nri2496 · Cited by 433
Autophagy is essential for effector CD8+ T cell survival and memory formation
Xu, X., Araki, K., Li, S., Han, J., Ye, L., Tan, W. G., Konieczny, B. T., Bruinsma, M. W., Martinez, J., Pearce, E. L., et al. (2014) · Nature Immunology · doi:10.1038/ni.3025 · Cited by 438
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“…profile in memory CD8+ T cells is due to remethylation rather than selective death of terminal effector cells, we measured the methylation status in day 8 terminal effector (Klrg1hiIL7Ralo) and memory precursor (Klrg1loIL7Rahi) subsets (Figure 2D; Kaech et al., 2003; Sarkar et al., 2008).”
BackgroundResultInfluentialSelf-citationmTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation
Pollizzi, K. N., Patel, C. H., Sun, I., Oh, M. H., Waickman, A. T., Wen, J., Delgoffe, G. M., & Powell, J. D. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77746 · Cited by 417
Four functionally distinct populations of human effector-memory CD8+ T lymphocytes
Romero, P., Zippelius, A., Kurth, I., Pittet, M. J., Touvrey, C., Iancu, E. M., Corthesy, P., Devevre, E., Speiser, D. E., & Rufer, N. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.7.4112 · Cited by 405
“Finally, both CM and EM1 T cell subsets express high levels of the IL-7R chain (CD127) necessary to memory cell survival (40), but only low levels of effector molecules such as IFN- , granzyme B, and perforin.”
BackgroundT cells and viral persistence: lessons from diverse infections
Klenerman, P., & Hill, A. B. (2005) · Nature Immunology · doi:10.1038/ni1241 · Cited by 407
“The remaining cells differentiate into memory T cells, maintained in the absence of antigen by cytokine-driven homeostatic proliferatio”
BackgroundYang, C. Y., Best, J. A., Knell, J., Yang, E., Sheridan, A. D., Jesionek, A. K., Li, H. S., Rivera, R. R., Lind, K. C., D’Cruz, L. M., et al. (2011) · Nature Immunology · doi:10.1038/ni.2158 · Cited by 411
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Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination
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“Enhanced resistance in DC-LLO+LM mice Antigen-specific CD8 + T cells at day 68 after booster infection of DC-LLO+LM and LM+LM mice showed a memory phenotype (CD44 hi , interleukin (IL)-7 receptor–positiv”
BackgroundCytotoxic T Lymphocyte Therapy for Epstein-Barr Virus+ Hodgkin's Disease
Bollard, C. M., Aguilar, L. K., Straathof, K. C. M., Gahn, B., Huls, M. H., Rousseau, A., Sixbey, J. W., Gresik, M. V., Carrum, G., Hudson, M. M., et al. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040890 · Cited by 387
Diversity in T Cell Memory: An Embarrassment of Riches
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“These cells also show enhanced ability to subsequently upregulate IL-7Ra, which is important for memory T cell survival (Buentke et al., 2006; Kaech et al., 2003; Schluns et al., 2000) and to differentiate into a long-lived pool of Tcm cells.”
Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment
Lévy, Y., Lacabaratz, C., Weiss, L., Viard, J., Goujard, C., Lelièvre, J., Boué, F., Molina, J., Rouzioux, C., Avettand-Fènoël, V., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38052 · Cited by 393
COOPERATION BETWEEN CD4+AND CD8+T CELLS: When, Where, and How
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“Class I MHC tetramers were generated as described previously (Kaech et al., 2003).”
InfluentialSelf-citationFlip the coin: IL-7 and IL-7R in health and disease
Barata, J. T., Durum, S. K., & Seddon, B. P. (2019) · Nature Immunology · doi:10.1038/s41590-019-0479-x · Cited by 377
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“The IL-7 receptor (CD127) is involved in homeostatic proliferation and survival of memory T cell precursors (46), while CD57 is indicative of cell senescence, failure to proliferate, and susceptibility to activationinduced cell death (47,48).”
BackgroundLaidlaw, B. J., Zhang, N., Marshall, H. D., Staron, M. M., Guan, T., Hu, Y., Cauley, L. S., Craft, J. E., & Kaech, S. M. (2014) · Immunity · doi:10.1016/j.immuni.2014.09.007 · Cited by 382
Self-citationImmunosenescence: what does it mean to health outcomes in older adults?
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“The action of KGF is to enhance IL-7 production in the thymus, by binding to the KGF receptors on thymic epithelial cells [37,38], suggesting it might have multiple beneficial effects, given the critical role of IL-7 in the development and maintenance of T cells, including long-lived memory cells, following vaccinatio…”
BackgroundTranscriptional insights into the CD8+ T cell response to infection and memory T cell formation
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The Yellow Fever Virus Vaccine Induces a Broad and Polyfunctional Human Memory CD8+ T Cell Response
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“CD127 (IL-7R ) has been shown earlier to be an important marker that is downregulated on effectors and selectively reexpressed on a subset destined to form precursors of the memory pool (10, 35).”
Self-citationA single naive CD8+ T cell precursor can develop into diverse effector and memory subsets.
Stemberger, C., Huster, K., Koffler, M., Anderl, F., Schiemann, M., Wagner, H., & Busch, D. (2007) · Immunity · doi:10.1016/j.immuni.2007.10.012 · Cited by 394
Cell biology of IL-7, a key lymphotrophin
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“[94] Kaech SM, et al.”
BackgroundTLR agonists: our best frenemy in cancer immunotherapy
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“The costimulatory effects of TLR signaling are associated with increased PI3K and PKC signaling [40, 66].”
BackgroundTakemoto, N., Intlekofer, A. M., Northrup, J. T., Wherry, E. J., & Reiner, S. L. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.11.7515 · Cited by 339
“4A), which has been suggested to mark memory precursors during acute infection (22, 23).”
BackgroundSelf-citation
Metadata
- Authors
- Kaech, S. M., Tan, J. T., Wherry, E. J., Konieczny, B. T., Surh, C. D., & Ahmed, R.
- Affiliations
- Emory University (US)
- Scripps Research Institute (US)
- Corresponding author
- Ahmed, Rafi
- Venue
- Nature Immunology
- Published
- 2003-11-16
- Volume
- 4
- Issue
- 12
- Pages
- 1191-1198
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W1974842026
- Cited by
- 1,830
- References
- 48
- Citations by year
- 2026: 41 · 2025: 57 · 2024: 42 · 2023: 63 · 2022: 67 · 2021: 69 · 2020: 67 · 2019: 70 · 2018: 56 · 2017: 59 · 2016: 77 · 2015: 73 · 2014: 73 · 2013: 96 · 2012: 91
- FWCI
- 30.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- CD127, CD8+ T cells, effector T cells, memory T cells, apoptosis, adoptive transfer, viral infection, protective immunity, memory T cell generation
- MeSH terms
- Animals, Antigens, Surface, Cell Differentiation, Immunologic Memory, Lymphocyte Activation, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Transgenic, Signal Transduction, Gene Expression, T-Lymphocyte Subsets, CD8-Positive T-Lymphocytes, Cell Lineage, Adoptive Transfer, Receptors, Interleukin-7, Oligonucleotide Array Sequence Analysis, Mice
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