Breakdown in repression of IFN-γ mRNA leads to accumulation of self-reactive effector CD8+ T cells.
Tight regulation of virus-induced cytotoxic effector CD8(+) T cells is essential to prevent immunopathology. Naturally occurring effector CD8(+) T cells, with a KLRG1(hi) CD62L(lo) phenotype typical of short-lived effector CD8(+) T cells (SLECs), can be found in increased numbers in autoimmune-prone mice, most notably in mice homozygous for the san allele of Roquin. These SLEC-like cells were able to trigger autoimmune diabetes in a susceptible background. When Roquin is mutated (Roquin(san)), effector CD8(+) T cells accumulate in a cell-autonomous manner, most prominently as SLEC-like effectors. Excessive IFN-γ promotes the accumulation of SLEC-like cells, increases their T-bet expression, and enhances their granzyme B production in vivo. We show that overexpression of IFN-γ was caused by failed posttranscriptional repression of Ifng mRNA. This study identifies a novel mechanism that prevents accumulation of self-reactive cytotoxic effectors, highlighting the importance of regulating Ifng mRNA stability to maintain CD8(+) T cell homeostasis and prevent CD8-mediated autoimmunity.
Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Pheh-Ping
PP
Chang
Sau K
SK
Lee
Xin
X
Hu
Gayle
G
Davey
Guowen
G
Duan
Jae-Ho
JH
Cho
Guna
G
Karupiah
Jonathan
J
Sprent
William R
WR
Heath
Edward M
EM
Bertram
Carola G
CG
Vinuesa
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D002449:Cell Aggregation / Q000235:genetics / Q000276:immunology*; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000276:immunology; D020871:RNA Stability / Q000276:immunology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000235:genetics; D011971:Receptors, Immunologic; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D007166:Immunosuppressive Agents; C113413:KLRG1 protein, human; D037181:Lectins, C-Type; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D015534:Trans-Activators; D007371:Interferon-gamma; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases