The co-stimulatory molecule GITR intrinsically enhances type 1 and follicular helper CD4 T cell responses to establish early control of a persistent viral infection and potentiate the late humoral response (IRC9P.700)

Abstract

Abstract During persistent infection, the immune system must be tightly regulated to balance immune control against pathology. The glucocorticoid-induced TNFR (GITR) is an important co-stimulatory molecule that plays a critical CD4 T cell-intrinsic role in the control of a mouse model of chronic viral infection, LCMV clone 13. 8 days post-infection (dpi) of wild-type (WT) and GITR-/- mice revealed that GITR-/- mice have 2-fold fewer LCMV-specific CD8 T cells, with higher PD-1 and Tim-3 levels. These defects became more striking at 45 dpi, when GITR-/- mice have a ~9-fold deficit in IFNγ+CD107+TNF+ CD8 T cells. GITR-/- mice had impaired viral control, with 35- and 10- fold higher viral load in the kidney at 8 and 45 dpi, respectively. Depletion of CD4 cells largely abrogated the differences between WT and GITR-/- mice at 8 dpi, suggesting that CD4 T cells underscore the impaired T cell responses of GITR-/- mice. GITR-/- mice have 3-4-fold fewer IFNγ+ and IL-2+ Th1 cells at 8 dpi. Using DEREG mice, we found that the compromised immunity and viral control in GITR-/- mice are independent of Foxp3+ Tregs. GITR-/- mice also had 2-fold fewer follicular helper (Tfh) cells at 21-45 dpi, with concomitant impairment in LCMV-specific IgG titres. Mixed bone marrow chimeras revealed a CD4 T cell-intrinsic role for GITR in potentiating Th1 and Tfh responses. Our findings reveal a critical role for GITR in co-stimulation of CD4 helper T cell subsets for optimal cell-mediated and humoral immunity.