The role of the T-cell receptor (TCR) in the generation of lung CD4+ tissue-resident memory T cells (TRM) following influenza infection 2307595

Abstract

Abstract Introduction Upon initial antigen encounter, anti-influenza T cells infiltrate the lung and form tissue-resident memory T cells (TRM), that provide a rapid response to antigen re-encounter. While the mechanisms driving lung CD8+ TRM formation are well defined, CD4+ TRM are less understood. Methods In order to define the role of the TCR in the formation of CD4+ TRM in the lung after influenza infection, we employed a novel TCR transgenic mouse line, GPB1, that expresses a fixed TCRB chain derived from a TCR specific for the MHC Class II-restricted epitope of the LCMV glycoprotein, GP61-80, paired to a polyclonal TCRa repertoire, crossed to a mouse expressing a Nur77-GFP reporter to monitor TCR signal strength. We transferred GPB1 T cells into WT hosts followed by a primary or heterologous secondary challenge with recombinant PR8 expressing GP61-80 (PR8-gp61), enabling us to track T cells across a broad range of TCR avidity and signal strength. Results Lung-infiltrating effector CD4+ T cells displayed higher TCR avidity and enhanced TCR signal strength compared to those in the mediastinal lymph nodes (medLN). This was true for both primary PR8-gp61 infection as well as heterologous secondary PR8-gp61 challenge biased towards Tfh-like (due to prior protein immunization with recombinant GP) or Th1-like (due to prior LCMV infection) effector responses in the lung. Resulting lung CD4+ TRM also skewed towards high avidity as compared to medLN. Enhanced TCR avidity and signal strength in the lung was associated with induced expression of the integrin CD49b and the chemokine receptor CXCR6. Conclusion We conclude that strong TCR signaling in high avidity CD4+ T cells drives lung-homing effector T cell responses and establishment of TRM. Future work will establish the mechanistic link between TCR signal strength and the upregulation of molecules required for homing to or retention within the lung. Funding Source R01AI194555, T32AI138945 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)