Differential effect of GITR on lung effector T cell subpopulations during influenza infection

Abstract

Abstract Influenza remains an important global threat. Tissue resident memory T cells (Trm) are critical in protection against influenza, and it is important to identify key mechanisms regulating their formation and persistence. GITR, an NF-κB activating TNFR family member, is required on CD8 T cells for maximal responses against influenza. Our recent work (Mucosal Immunology, doi:10.1038/s41385-018-0105-5) provided evidence that GITRL on monocyte-derived inflammatory APCs provides crucial signals through GITR on T cells in the lung tissue (termed Signal 4), allowing effector T cell accumulation and optimal Trm formation during influenza infection in mice. During influenza infection, responding lung T cells are heterogeneous, some will give rise to terminally differentiated effector cells, while others will become Trm. It remains unknown how GITR affects these subpopulations. To address this issue, we characterized these CD8 T cell subsets using markers Ly6C, KLRG1, T-bet, and the chemokine receptor CX3CR1. By staining with Ly6C and CX3CR1, we identified three different CD8 T cell subsets with differential expression of Ly6C and CX3CR1 (Ly6ChiCX3CR1 hi, Ly6ChiCX3CR1 lo, Ly6CloCX3CR1 lo). Ly6ChiCX3CR1 hi CD8 T cell subset likely represents the most terminally differentiated effector cells as they have the highest expression of KLRG1 and T-bet. Using the adoptive transfer of transgenic OT-I cells, we discovered that there is a larger loss of the Ly6CloCX3CR1 loCD8 T cell in the absence of GITR when compared to the other two subsets. We are currently investigating which of the three subsets give rise to the lung Trm population after influenza infection and the timing and nature of the GITR-dependent signals involved. Funded by CIHR:FDN143250