The Role of the Costimulatory TNFR Family Member GITR in T Cell Immunity During an Acute Respiratory Infection

T cells play a critical role in control of influenza virus, a major human pathogen. Glucocorticoid-induced TNFR-related Protein (GITR), a prosurvival member of the TNFR family, contributes to maximal CD8 T cell responses and protects mice from death upon severe influenza infection. In this thesis, I demonstrate that during influenza infection, GITR ligand (GITRL) is mainly expressed by a group of monocyte-derived tissue infiltrating cells known as inflammatory antigen presenting cells (InfAPC). I show that both GITR and GITRL are detected early in the mediastinal lymph node (mLN) and in the lung tissue when T cells start to accumulate after influenza infection. By detecting phospho-signals downstream of GITR, I show that InfAPC likely provide crucial signals through GITR on T cells in the mLN and afterwards in the lung. This signal is critical for the accumulation of lung effector CD4 and CD8 T cells as well as optimal formation of lung CD4 and CD8 tissue-resident memory T cells (Trm) after influenza infection. The signals that GITR delivers for effector T cell and Trm accumulation most likely occur at the effector phase of the response since GITRL expression is mainly confined to the first week of influenza infection. Thus, I investigated how GITR affects effector T cell subpopulations during influenza infection. Ly6C expression defines two effector CD4 T cell subsets while Ly6C and CX3CR1 expression defines three effector CD8 T cell subpopulations. In CD8 T cells, GITR affects the accumulation of all three subsets, with a predominant effect on the least differentiated subset. GITR also selectively upregulates CXCR6 on the less differentiated CX3CR1lo CD8 T cell subsets. GITR affects the accumulation of both CD4 T cell subsets, but selectively upregulates CD127 in the least differentiated CD4 T cell subpopulation which shows a preference for entry into the lung parenchyma. Together, this thesis demonstrates that during influenza infection GITR costimulation in the lung plays an important role in sustaining both highly differentiated effector T cells and Trm precursors, but with differential effects on effector T cell subpopulations. This signal is also critical for optimal formation of lung CD4 and CD8 Trm.Ph.D