IL-7 Signaling Must Be Intermittent, Not Continuous, During CD8⁺ T Cell Homeostasis to Promote Cell Survival Instead of Cell Death

Overview

Journal Nat Immunol

Date 2012 Dec 18

PMID 23242416

Citations 77

Authors

Motoko Y Kimura

Leonid A Pobezinsky

Terry I Guinter

Julien Thomas

Anthony Adams

Jung-Hyun Park

XuGuang Tai

Alfred Singer

Affiliations

Soon will be listed here.

Abstract

The maintenance of naive CD8(+) T cells is necessary for lifelong immunocompetence but for unknown reasons requires signaling via both interleukin 7 (IL-7) and the T cell antigen receptor (TCR). We now report that naive CD8(+) T cells required IL-7 signaling to be intermittent, not continuous, because prolonged IL-7 signaling induced naive CD8(+) T cells to proliferate, produce interferon-γ (IFN-γ) and undergo IFN-γ-triggered cell death. Homeostatic engagement of the TCR interrupted IL-7 signaling and thereby supported the survival and quiescence of CD8(+) T cells. However, CD8(+) T cells with insufficient TCR affinity for self ligands received prolonged IL-7 signaling and died during homeostasis. In this study we identified regulation of the duration of IL-7 signaling by homeostatic engagement of the TCR as the basis for in vivo CD8(+) T cell homeostasis.

Citing Articles

Tumor cells ectopically expressing the membrane-bound form of IL-7 develop an antitumor immune response efficiently in a colon carcinoma model.

Shin H, Kim H, Kwon S, Lee H, Lee J, Kim Y Mol Cells. 2025; 48(2):100175.

PMID: 39743142 PMC: 11873615. DOI: 10.1016/j.mocell.2024.100175.

Mechanisms governing bystander activation of T cells.

Yosri M, Dokhan M, Aboagye E, Moussawy M, Abdelsamed H Front Immunol. 2024; 15:1465889.

PMID: 39669576 PMC: 11635090. DOI: 10.3389/fimmu.2024.1465889.

Lrp10 suppresses IL7R limiting CD8 T cell homeostatic expansion and anti-tumor immunity.

Russell J, Chen L, Liu A, Wang J, Ghosh S, Zhong X EMBO Rep. 2024; 25(8):3601-3626.

PMID: 38956225 PMC: 11315911. DOI: 10.1038/s44319-024-00191-w.

HA-1-targeted T-cell receptor T-cell therapy for recurrent leukemia after hematopoietic stem cell transplantation.

Krakow E, Brault M, Summers C, Cunningham T, Biernacki M, Black R Blood. 2024; 144(10):1069-1082.

PMID: 38683966 PMC: 11406181. DOI: 10.1182/blood.2024024105.

Cellular metabolism regulates the differentiation and function of T-cell subsets.

Ma S, Ming Y, Wu J, Cui G Cell Mol Immunol. 2024; 21(5):419-435.

PMID: 38565887 PMC: 11061161. DOI: 10.1038/s41423-024-01148-8.

References

Yu Q, Erman B, Park J, Feigenbaum L, Singer A . IL-7 receptor signals inhibit expression of transcription factors TCF-1, LEF-1, and RORgammat: impact on thymocyte development. J Exp Med. 2004; 200(6):797-803. PMC: 2211960. DOI: 10.1084/jem.20032183. View

Bream J, Hodge D, Gonsky R, Spolski R, Leonard W, Krebs S . A distal region in the interferon-gamma gene is a site of epigenetic remodeling and transcriptional regulation by interleukin-2. J Biol Chem. 2004; 279(39):41249-57. DOI: 10.1074/jbc.M401168200. View

Wofford J, Wieman H, Jacobs S, Zhao Y, Rathmell J . IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood. 2007; 111(4):2101-11. PMC: 2234050. DOI: 10.1182/blood-2007-06-096297. View

Takada K, Jameson S . Self-class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levels. J Exp Med. 2009; 206(10):2253-69. PMC: 2757867. DOI: 10.1084/jem.20082553. View

Schluns K, Kieper W, Jameson S, Lefrancois L . Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nat Immunol. 2001; 1(5):426-32. DOI: 10.1038/80868. View

Nesic D, Vukmanovic S . MHC class I is required for peripheral accumulation of CD8+ thymic emigrants. J Immunol. 1998; 160(8):3705-12. View

Mazzucchelli R, Durum S . Interleukin-7 receptor expression: intelligent design. Nat Rev Immunol. 2007; 7(2):144-54. DOI: 10.1038/nri2023. View

Park J, Yu Q, Erman B, Appelbaum J, Montoya-Durango D, Grimes H . Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity. 2004; 21(2):289-302. DOI: 10.1016/j.immuni.2004.07.016. View

Swainson L, Kinet S, Mongellaz C, Sourisseau M, Henriques T, Taylor N . IL-7-induced proliferation of recent thymic emigrants requires activation of the PI3K pathway. Blood. 2006; 109(3):1034-42. DOI: 10.1182/blood-2006-06-027912. View

10.

Lee I, Li W, Hisert K, Ivashkiv L . Inhibition of interleukin 2 signaling and signal transducer and activator of transcription (STAT)5 activation during T cell receptor-mediated feedback inhibition of T cell expansion. J Exp Med. 1999; 190(9):1263-74. PMC: 2195684. DOI: 10.1084/jem.190.9.1263. View

11.

Polic B, Kunkel D, Scheffold A, Rajewsky K . How alpha beta T cells deal with induced TCR alpha ablation. Proc Natl Acad Sci U S A. 2001; 98(15):8744-9. PMC: 37506. DOI: 10.1073/pnas.141218898. View

12.

Seddon B, Zamoyska R . Regulation of peripheral T-cell homeostasis by receptor signalling. Curr Opin Immunol. 2003; 15(3):321-4. DOI: 10.1016/s0952-7915(03)00049-9. View

13.

Markiewicz M, Brown I, Gajewski T . Death of peripheral CD8+ T cells in the absence of MHC class I is Fas-dependent and not blocked by Bcl-xL. Eur J Immunol. 2003; 33(10):2917-26. DOI: 10.1002/eji.200324273. View

14.

Refaeli Y, Van Parijs L, Alexander S, Abbas A . Interferon gamma is required for activation-induced death of T lymphocytes. J Exp Med. 2002; 196(7):999-1005. PMC: 2194022. DOI: 10.1084/jem.20020666. View

15.

Vivien L, Benoist C, Mathis D . T lymphocytes need IL-7 but not IL-4 or IL-6 to survive in vivo. Int Immunol. 2001; 13(6):763-8. DOI: 10.1093/intimm/13.6.763. View

16.

Surh C, Sprent J . Homeostasis of naive and memory T cells. Immunity. 2008; 29(6):848-62. DOI: 10.1016/j.immuni.2008.11.002. View

17.

Tomita Y, Bilim V, Hara N, Kasahara T, Takahashi K . Role of IRF-1 and caspase-7 in IFN-gamma enhancement of Fas-mediated apoptosis in ACHN renal cell carcinoma cells. Int J Cancer. 2003; 104(4):400-8. DOI: 10.1002/ijc.10956. View

18.

Pyo C, Lee S, Choi S . Oxidative stress induces PKR-dependent apoptosis via IFN-gamma activation signaling in Jurkat T cells. Biochem Biophys Res Commun. 2008; 377(3):1001-6. DOI: 10.1016/j.bbrc.2008.10.103. View

19.

Tan J, Dudl E, Leroy E, Murray R, Sprent J, Weinberg K . IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc Natl Acad Sci U S A. 2001; 98(15):8732-7. PMC: 37504. DOI: 10.1073/pnas.161126098. View

20.

Goldrath A, Bevan M . Selecting and maintaining a diverse T-cell repertoire. Nature. 1999; 402(6759):255-62. DOI: 10.1038/46218. View