Memory CD8 T cells are vulnerable to chronic IFN-γ signals but not to CD4 T cell deficiency in MHCII-deficient mice

The mechanisms by which the number of memory CD8 T cells is stably maintained remains incompletely understood. It has been postulated that maintaining them requires help from CD4 T cells, because adoptively transferred memory CD8 T cells persist poorly in MHC class II (MHCII)-deficient mice. Here we show that chronic interferon-gamma signals, not CD4 T cell-deficiency, are responsible for their attrition in MHCII-deficient environments. Excess IFN-gamma is produced primarily by endogenous colonic CD8 T cells in MHCII-deficient mice. IFN-gamma neutralization restores the number of memory CD8 T cells in MHCII-deficient mice, whereas repeated IFN-gamma administration or transduction of a gain-of-function STAT1 mutant reduces their number in wild-type mice. CD127high memory cells proliferate actively in response to IFN-gamma signals, but are more susceptible to attrition than CD127low terminally differentiated effector memory cells. Furthermore, single-cell RNA-sequencing of memory CD8 T cells reveals proliferating cells that resemble short-lived, terminal effector cells and documents global downregulation of gene signatures of long-lived memory cells in MHCII-deficient environments. We propose that chronic IFN-gamma signals deplete memory CD8 T cells by compromising their long-term survival and by diverting self-renewing CD127high cells toward terminal differentiation. Memory CD8+ T cells persist poorly in MHCII-deficient mice. Here the authors show that this CD8+ T cell attrition is not caused by a lack of CD4+ T cell help, as previously proposed, but by chronic IFN-gamma signals derived from endogenous colonic CD8+ T cells.