Characterization of viral- and fungal-reactive CD4+ T cells in healthy and diseased

CD4⁺ T lymphocytes are central regulators of adaptive immunity, coordinating protective immune responses while maintaining tolerance to harmless antigens. Their antigen specificity, diversity and functional properties are poorly characterized. This thesis is a cumulative work of three manuscripts that cover the investigation of antigen-specific CD4⁺ T cell responses in the contexts of SARS-CoV2 vaccination and chronic intestinal inflammation, with focus on the roles of pre-existing T cell repertoires, antigen specificity and cross reactivity. The first study demonstrates that the quality of immune responses to SARS-CoV-2-vaccination is strongly influenced by the pre-existing CD4⁺ T cell repertoire. Robust immunity is associated with the expansion of high-avidity spike-specific T cells derived from the naïve repertoire, whereas increased pre-existing memory T cells and aging can impair T cell expansion and reduce vaccine responsiveness. The second study identifies commensal and food-derived yeasts as important drivers of aberrant CD4⁺ T cell responses in Crohn’s disease. Yeast-reactive T cells display a cytotoxic T_H1 phenotype, undergo clonal expansion and exhibit broad cross-reactivity, suggesting that repeated exposure to conserved fungal antigens can contribute to chronic intestinal inflammation. The third study shows that Candida albicans-specific T_H17 cells recognize a restricted set of fungal antigens and are primarily resident in the oral mucosa under homeostatic conditions. In Crohn’s disease, these cells accumulate in the intestine while retaining antigen specificity but acquire a pathogenic-T_H17 signature. Together, these findings demonstrate that the composition of the CD4⁺ T cell repertoire are key determinants of protective immunity, providing insights that may guide the development of targeted therapies.