<p>Major histocompatibility complex (MHC) class I and class II molecules present antigens to CD8⁺ and CD4⁺ T cells respectively. Here we uncover a previously unrecognized role for MHC class I in modulating CD4⁺ T cell-mediated immunity. In allogeneic graft-versus-host disease and tumor models, 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 suggest that this was because of heightened sensitivity to enhanced ferroptosis of the target cells. In large human transcriptomic and sequencing datasets, a role for CD4⁺ T cells in enhancing immune checkpoint blocker-mediated responses in persons with melanoma and mismatch-repair-deficient colon cancers that have downregulated MHC class I was suggested. These findings revise and expand the known role of MHC class I in CD8⁺ T cell and natural killer cell immunity and demonstrate a previously unrecognized role in CD4⁺ T cell-mediated cancer and alloimmunity.</p>