Development of MHC Class I Blocking Peptides to Target Metabolic Dysfunction-Associated Steatohepatitis CD8 ⁺ T Cell Activation

MHC class I molecules play a crucial role in the immune system by presenting peptides derived from intracellular proteins to cytotoxic T lymphocytes (CTLs). This process is essential for immune surveillance and eliminating infected or malignant cells. In some diseases, the immune system fails to recognize and eliminate abnormal cells, leading to disease progression. Under conditions of metabolic dysfunction-associated steatohepatitis (MASH), subsets of CD8 ⁺ T cells have been identified as pathogenic, leading to inflammation and fibrosis. Therefore, explicitly targeting factors responsible for T cell activation may be necessary to prevent the onset of MASH and future complications such as cirrhosis or hepatocellular carcinoma. We have identified a specific MHC class I antigen that activates hepatic and splenic CD8 ⁺ T cells isolated from MASH mice. To specifically target the antigen, we developed two MHC H2-K ^b blocking peptides, MHCP3 and MHCP5, that competitively inhibit the Ncf2 peptide from binding to H2-K ^b and reduce activation and proliferation of CD8 ⁺ T cells. By inhibiting the recognition of specific antigens, these blocking peptides may prevent the activation of CD8 ⁺ T cells and progression of MASH.