MHC Class I on Target Cells Regulates CD4+ T cell-mediated Immunity

The central tenet of T cell immune surveillance is that MHC class I and class II molecules present antigens to CD8+ and CD4+ T cells, respectively. Here, we uncover a surprising and previously unrecognized role for MHC class I in modulating CD4+ T cell-mediated immunity. Using multiple in vivo models of allogeneic graft-versus-host disease (GVHD) and tumor immunity, we demonstrate that the absence of MHC class I on target cells significantly increases their susceptibility to CD4+ T cell cytotoxicity. Transcriptomic and functional studies indicate this heightened sensitivity to enhanced ferroptosis of the target cells without affecting the degree of CD4+ T cell activation or inflammatory responses. The experimental results are corroborated utilizing multiple large human transcriptomic and sequencing datasets that suggest a role for CD4+ T cells in enhancing immune checkpoint blocker-mediated responses in patients with melanoma and mismatch repair-deficient (MMRd) colon cancers that have downregulated MHC class I. These findings revise and expand the known role of MHC class I in CD8+ T cell and NK cell immunity and demonstrate a previously unrecognized role in CD4+ T cell-mediated cancer and alloimmunity.