FRCs are structural cells that construct the parenchyma of secondary lymphoid organs while enacting a range of profound immunomodulatory functions. Mouse FRCs notably protect themselves and the lymphoid organ infrastructure from T-cell mediated immunopathology through a range of MHC-dependent and independent mechanisms, including deletion of high-affinity autoreactive CD8+ T-cells, impairment of CD4+ T-cell function, induction of Tregs, and dampening T cell proliferation.
Here, we report that human FRCs are equipped to acquire and present antigens to CD8+ T cells. Flow cytometry and RNA-Seq showed that human FRCs express MHC class I as well as low but detectable levels of CIITA, CD74 and other markers of antigen presentation in steady state conditions, and that this is strongly upregulated by treatment with IFNg, as described. Through flow cytometry and immunofluorescence microscopy, we then established that human FRCs readily acquired particulate antigens through phagocytosis and micropinocytosis, and that they are infected by Influenza A. Co-cultures of engineered CD8+ T-cells with HLA-matched or mismatched FRCs showed that human FRCs could stimulate antigen-specific CD8 T cells to upregulate CD69. We did not observe an ability to activate CD4+ T-cells in this system, with or without IFNg-stimulated upregulation of MHC class II. Since mouse FRCs are known to induce peripheral tolerance via MHC class I and II, the ability of human FRCs to acquire and present antigens, even if only to CD8 T cells, suggests that are likely to possess immunomodulatory functions. Further work will determine the fate of T cells activated by antigen-bearing FRCs. Collectively, we illuminate human FRCs as effective antigen acquirers, and APCs to CD8 T cells.