Autocrine IFN-γ Promotes Naive CD8 T Cell Differentiation and Synergizes with IFN-α to Stimulate Strong Function

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2012 Jun 19

PMID 22706089

Citations 57

Authors

Julie M Curtsinger

Pujya Agarwal

Debra C Lins

Matthew F Mescher

Affiliations

Soon will be listed here.

Abstract

Autocrine IFN-γ signaling is important for CD4 differentiation to Th1 effector cells, but it has been unclear whether it contributes to CD8 T cell differentiation. We show in this paper that naive murine CD8 T cells rapidly and transiently produce low levels of IFN-γ upon stimulation with Ag and B7-1, with production peaking at ∼8 h and declining by 24 h. The autocrine IFN-γ signals for upregulation of expression of T-bet and granzyme B and induces weak cytolytic activity and effector IFN-γ production. IFN-α acts synergistically with IFN-γ to support development of strong effector functions, whereas IL-12 induces high T-bet expression and strong function in the absence of IFN-γ signaling. Thus, IFN-γ is not only an important CD8 T cell effector cytokine, it is an autocrine/paracrine factor whose contributions to differentiation vary depending on whether the response is supported by IL-12 or type I IFN.

Citing Articles

Development of a Competitive Nutrient-Based T-Cell Immunotherapy Designed to Block the Adaptive Warburg Effect in Acute Myeloid Leukemia.

Cao H, Xiao J, Baylink D, Nguyen V, Shim N, Lee J Biomedicines. 2024; 12(10).

PMID: 39457563 PMC: 11504511. DOI: 10.3390/biomedicines12102250.

SLAMF7 (CD319) on activated CD8 T cells transduces environmental cues to initiate cytotoxic effector cell responses.

Lingel H, Fischer L, Remstedt S, Kuropka B, Philipsen L, Han I Cell Death Differ. 2024; 32(3):561-572.

PMID: 39390117 PMC: 11893764. DOI: 10.1038/s41418-024-01399-y.

Anabolic deficits and divergent unfolded protein response underlie skeletal and cardiac muscle growth impairments in the Yoshida hepatoma tumor model of cancer cachexia.

Belcher D, Kim N, Navarro-Llinas B, Moller M, Lopez-Soriano F, Busquets S Physiol Rep. 2024; 12(18):e70044.

PMID: 39294861 PMC: 11410559. DOI: 10.14814/phy2.70044.

SOCS1 is a critical checkpoint in immune homeostasis, inflammation and tumor immunity.

Bidgood G, Keating N, Doggett K, Nicholson S Front Immunol. 2024; 15:1419951.

PMID: 38947335 PMC: 11211259. DOI: 10.3389/fimmu.2024.1419951.

Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cells.

Kennewick K, Yamaguchi Y, Gibson J, Gerdts E, Jeang B, Tilakawardane D Mol Ther Oncol. 2024; 32(2):200789.

PMID: 38939825 PMC: 11208731. DOI: 10.1016/j.omton.2024.200789.

References

Curtsinger J, Schmidt C, Mondino A, Lins D, Kedl R, Jenkins M . Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T cells. J Immunol. 1999; 162(6):3256-62. View

Curtsinger J, Gerner M, Lins D, Mescher M . Signal 3 availability limits the CD8 T cell response to a solid tumor. J Immunol. 2007; 178(11):6752-60. DOI: 10.4049/jimmunol.178.11.6752. View

Curtsinger J, Valenzuela J, Agarwal P, Lins D, Mescher M . Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J Immunol. 2005; 174(8):4465-9. DOI: 10.4049/jimmunol.174.8.4465. View

Ben-Sasson S, Hu-Li J, Quiel J, Cauchetaux S, Ratner M, Shapira I . IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc Natl Acad Sci U S A. 2009; 106(17):7119-24. PMC: 2678417. DOI: 10.1073/pnas.0902745106. View

LeibundGut-Landmann S, Osorio F, Brown G, Reis e Sousa C . Stimulation of dendritic cells via the dectin-1/Syk pathway allows priming of cytotoxic T-cell responses. Blood. 2008; 112(13):4971-80. DOI: 10.1182/blood-2008-05-158469. View

Hu X, Ivashkiv L . Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity. 2009; 31(4):539-50. PMC: 2774226. DOI: 10.1016/j.immuni.2009.09.002. View

Glimcher L, Townsend M, Sullivan B, Lord G . Recent developments in the transcriptional regulation of cytolytic effector cells. Nat Rev Immunol. 2004; 4(11):900-11. DOI: 10.1038/nri1490. View

Pearce E, Shen H . Generation of CD8 T cell memory is regulated by IL-12. J Immunol. 2007; 179(4):2074-81. DOI: 10.4049/jimmunol.179.4.2074. View

Hu X, Herrero C, Li W, Antoniv T, Falck-Pedersen E, Koch A . Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation. Nat Immunol. 2002; 3(9):859-66. DOI: 10.1038/ni828. View

10.

Szabo S, Sullivan B, Stemmann C, Satoskar A, Sleckman B, Glimcher L . Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science. 2002; 295(5553):338-42. DOI: 10.1126/science.1065543. View

11.

Sercan O, Stoycheva D, Hammerling G, Arnold B, Schuler T . IFN-gamma receptor signaling regulates memory CD8+ T cell differentiation. J Immunol. 2010; 184(6):2855-62. DOI: 10.4049/jimmunol.0902708. View

12.

Pearce E, Mullen A, Martins G, Krawczyk C, Hutchins A, Zediak V . Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science. 2003; 302(5647):1041-3. DOI: 10.1126/science.1090148. View

13.

Pape K, Khoruts A, Mondino A, Jenkins M . Inflammatory cytokines enhance the in vivo clonal expansion and differentiation of antigen-activated CD4+ T cells. J Immunol. 1997; 159(2):591-8. View

14.

Zhou W, Chang S, Aune T . Long-range histone acetylation of the Ifng gene is an essential feature of T cell differentiation. Proc Natl Acad Sci U S A. 2004; 101(8):2440-5. PMC: 356969. DOI: 10.1073/pnas.0306002101. View

15.

Curtsinger J, Mescher M . Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol. 2010; 22(3):333-40. PMC: 2891062. DOI: 10.1016/j.coi.2010.02.013. View

16.

Schmidt C, Mescher M . Adjuvant effect of IL-12: conversion of peptide antigen administration from tolerizing to immunizing for CD8+ T cells in vivo. J Immunol. 1999; 163(5):2561-7. View

17.

Hogquist K, Jameson S, Heath W, Howard J, Bevan M, Carbone F . T cell receptor antagonist peptides induce positive selection. Cell. 1994; 76(1):17-27. DOI: 10.1016/0092-8674(94)90169-4. View

18.

Tewari K, Nakayama Y, Suresh M . Role of direct effects of IFN-gamma on T cells in the regulation of CD8 T cell homeostasis. J Immunol. 2007; 179(4):2115-25. DOI: 10.4049/jimmunol.179.4.2115. View

19.

Puliaev R, Nguyen P, Finkelman F, Via C . Differential requirement for IFN-gamma in CTL maturation in acute murine graft-versus-host disease. J Immunol. 2004; 173(2):910-9. DOI: 10.4049/jimmunol.173.2.910. View

20.

Aichele P, Unsoeld H, Koschella M, Schweier O, Kalinke U, Vucikuja S . CD8 T cells specific for lymphocytic choriomeningitis virus require type I IFN receptor for clonal expansion. J Immunol. 2006; 176(8):4525-9. DOI: 10.4049/jimmunol.176.8.4525. View