Major Histocompatibility Complex (MHC) and Fungal Antigen Presentation: Immunological Mechanisms and Their Role in Anti-Fungal Immunity

Cellular-mediated immunity against invasive fungal infections is fundamentally governed by Major Histocompatibility Complex (MHC) restriction, whereby T cells detect fungal invasion indirectly through peptide fragments displayed on host MHC molecules rather than by recognizing intact fungal pathogens. In contrast to B cells, which bind native microbial antigens, T lymphocytes monitor antigen-presenting cells for processed fungal peptides presented by MHC class I and class II molecules. This review examines the molecular mechanisms underlying fungal antigen processing and presentation, emphasizing the pivotal contributions of MHC class II-restricted CD4 T-helper (TH1/TH17) cells and cross-presented, MHC class I-restricted CD8 cytotoxic T lymphocytes to antifungal host defense. We also summarize key experimental approaches, including overlapping peptide libraries, ELISpot assays, and peptide–MHC multimers, for defining MHC function and identifying immunodominant fungal antigenic determinants. Evidence from representative pathogenic fungal antigens, including Asp f16, Crf1, Eng2, and the multivalent rCpa1 vaccine, highlights both the promise and complexity of achieving cross-protective cellular immunity. Importantly, amino acid sequence similarity alone is insufficient to predict T-cell cross-reactivity, indicating that computational prediction and experimental epitope mapping should be employed as complementary approaches for the accurate identification and validation of immunologically relevant epitopes. Finally, elucidating the molecular principles governing fungal peptide presentation establishes a rational foundation for the development of broadly protective epitope-based vaccines and next-generation immunotherapeutic strategies.