Role of GITR and its ligand in sustaining T cell responses against influenza infection

Abstract

Abstract Members of the TNFR family play a critical role in determining the magnitude of T cell responses against viral infections. Previous studies using TCR transgenic models showed that GITR, an NF-κB activating TNFR family member, is required intrinsically on CD8 T cells for maximal response against influenza virus. However, it remains unknown how GITR affects the overall endogenous T cell responses during influenza infection. Here, we examined the effect of GITR on endogenous T cell responses against influenza virus in competitive mixed bone marrow chimeras. We found that GITR is intrinsically required for the accumulation of antigen-specific CD4 and CD8 T cells in the lung and secondary lymphoid organs during influenza infection. GITR affected influenza PA224-233-specific CD8 T cells more dramatically than NP366-374-specific CD8 T cells. GITR also had a small positive effect on the number of Tregs. Among different APC subsets in the lung and its dLN, we observed highest GITRL expression on inflammatory DCs and inflammatory macrophages in both organs. Interestingly, we observed peak GITRL expression on these inflammatory subsets on day 3 and day 5 post-influenza infection in the lung but earlier in the dLN. The finding that GITRL is expressed on inflammatory APCs in the lung at the time when T cells enter the lung raises the possibility that GITRL plays a role in the lung tissue and not just in lymphoid organs. We are currently investigating when and where T cells receive signals through GITR, whether early in the dLN or later in the lung during influenza infection. A more thorough understanding of GITR/GITRL axis will provide valuable insights for influenza vaccine development.