GITR potentiates anti-viral T cell immunity by limiting regulatory T cells (P1015)

Abstract

Abstract The immune system must be tightly balanced to control infection while avoiding immune pathology. We investigated the role of the glucocorticoid-induced tumour necrosis factor receptor (GITR) during infection of mice with persistent lymphocytic choriomeningitis virus (LCMV) clone 13 infection. Infection of wild-type (WT) and GITR-/- mice with LCMV revealed that GITR plays a critical role in T cell responses and viral control. At 8 days post-infection (dpi), GITR-/- mice showed 3-fold fewer LCMV-specific CD8+ T cells, and these cells expressed significantly higher levels of inhibitory receptors Tim-3 and PD-1. These defects became more striking at 45 dpi, when there was also a substantial deficit in multifunctional (IFNγ+CD107a+TNFα+) CD8+ T cells in GITR-/- relative to WT mice. GITR-/- mice had 35-fold higher viral load in the kidney 8 dpi and 10-fold higher at day 45. Depletion of CD4+ T cells ameliorated the immune defects observed in GITR-/- mice, suggesting that a CD4+ population largely contributed to the GITR-/- phenotype. Strikingly, there were 4- to 5-fold more CD4+Foxp3+ regulatory T cells (Tregs) in the spleen and lymph nodes of GITR-/- mice 8 dpi, and only slightly more at 45 dpi. The dramatic increase in Treg numbers in GITR-/- mice 8 dpi is accompanied by a more suppressive phenotype. These studies demonstrate that GITR plays an indirect, yet critical role in CD8+ T cell responses and viral control by limiting the accumulation and function of Foxp3+ Tregs.