GITR Intrinsically Sustains Early Type 1 and Late Follicular Helper CD4 T Cell Accumulation to Control a Chronic Viral Infection

Cd4 t cells are critical for control of persistent infections; however,the key signals that regulate cd4 t help during chronic infection remain incompletely defined. while several studies have addressed the role of inhibitory receptors and soluble factors such as pd-1 and il-10,significantly less work has addressed the role of t cell co-stimulatory molecules during chronic viral infection. here we show that during a persistent infection with lymphocytic choriomeningitis virus (lcmv) clone 13,mice lacking the glucocorticoid-induced tumor necrosis factor receptor related protein (gitr) exhibit defective cd8 t cell accumulation,increased t cell exhaustion and impaired viral control. differences in cd8 t cells and viral control between gitr+/+ and gitr-/- mice were lost when cd4 t cells were depleted. moreover,mixed bone marrow chimeric mice,as well as transfer of lcmv epitope-specific cd4 or cd8 t cells,demonstrated that these effects of gitr are largely cd4 t cell-intrinsic. gitr is dispensable for initial cd4 t cell proliferation and differentiation,but supports the post-priming accumulation of ifnγ+il-2+ th1 cells,facilitating cd8 t cell expansion and early viral control. gitr-dependent phosphorylation of the p65 subunit of nf-κb as well as phosphorylation of the downstream mtorc1 target,s6 ribosomal protein,were detected at day three post-infection (p.i.),and defects in cd4 t cell accumulation in gitr-deficient t cells were apparent starting at day five p.i. consistently,we pinpoint il-2-dependent cd4 t cell help for cd8 t cells to between days four and eight p.i. gitr also increases the ratio of t follicular helper to t follicular regulatory cells and thereby enhances lcmv-specific igg production. together,these findings identify a cd4 t cell-intrinsic role for gitr in sustaining early cd8 and late humoral responses to collectively promote control of chronic lcmv clone 13 infection. © 2015 clouthier et al.