GITR/GITRL interaction in the lung provides signal 4 for T cell expansion and T-RM formation

Abstract Influenza remains an important global threat and it is important to identify key mechanisms by which the immune system handles the virus. TNFR family members can play a crucial role in determining the magnitude of T cell response against viral infections. Previous studies using TCR transgenic models showed that GITR, an NF-κB activating TNFR family member, is required on CD8 T cells for maximal response against influenza virus. However, it remains unknown how GITR affects the endogenous T cell response during influenza infection. Using competitive mixed bone marrow chimeras, we found that GITR is intrinsically required for the accumulation of effector CD4 and CD8 T cells in the lung and secondary lymphoid organs during influenza infection as well as for optimal lung Trm formation. GITR affected PA224–233-specific CD8 T cells more dramatically than NP366–374-specific CD8 T cells, which exhibited a compensatory increase in TCR affinity in the absence of GITR. GITRL expression was higher on inflammatory APCs compared to classical DCs with peak expression day 3 to day 5 post-infection in the lung. We observed peak GITR expression on CD4 T cells day 7 post-infection in the lung but earlier for CD8 T cells. The finding that both the receptor and the ligand are expressed in the lung raises the possibility that GITR costimulation plays an important role in the lung. Consistently, within the same mouse, lung GITR+/+OT-II had a higher level of pS6 (downstream of GITR signaling) than GITR−/− OT-II, providing evidence of GITR costimulation (signal 4) in the lung. In sum, GITR on CD4 and CD8 T cells plays an important role in their accumulation in the lung, likely through interaction with GITRL on inflammatory rather than classical DCs. Funded by CIHR:MOP133443