Breakdown in repression of IFN-gamma 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-gamma 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-gamma 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.
|Authors||Chang, P. P.; Lee, S. K.; Hu, X.; Davey, G.; Duan, G.; Cho, J. H.; Karupiah, G.; Sprent, J.; Heath, W. R.; Bertram, E. M.; Vinuesa, C. G.|
|Publisher Name||J IMMUNOL|
|Published Date||2012-07-15 00:00:00|
|OpenAccess Link||https://publications.gimr.garvan.org.au/download.php?11434_12017/12 Chang JI_.pdf|