Regulation of Immune Responses by Pharmacological Modulation of MHC-restricted Antigen Presentation

Major histocompatibility complex (MHC)-restricted antigen presentation is a fundamental process that initiates and shapes T cell-mediated immune responses. While most current immunomodulatory therapies target downstream signaling pathways of T cell activation, growing evidence highlights antigen presentation as a critical upstream determinant of T cell specificity, magnitude, and functional outcome. Pharmacological agents that modulate antigen processing, peptide loading, and MHC surface expression can profoundly alter T cell priming and immune responses. In this review, we briefly summarize the molecular mechanisms governing MHC class I- and class II-restricted antigen presentation, including cross-presentation by professional antigen-presenting cells. We then discuss emerging pharmacological modulators that regulate T cell responses by targeting MHC-restricted antigen presentation pathways, including calcineurin inhibitors, proteasome and immunoproteasome inhibitors, epigenetic regulators, endoplasmic reticulum stress modulators, and autophagy-targeting agents. By highlighting how these agents influence antigen processing and presentation independently of direct T cell signaling, we propose pharmacological modulation of MHC-restricted antigen presentation as an underexplored yet powerful strategy for immune intervention.