Enolase 1 of Candida albicans binds human CD4 + T cells and modulates naïve and memory responses

To obtain a better understanding of the biology behind life‐threatening fungal infections caused by Candida albicans , we recently conducted an in silico screening for fungal and host protein interaction partners. We report here that the extracellular domain of human CD4 binds to the moonlighting protein enolase 1 (Eno1) of C. albicans as predicted bioinformatically. By using different anti‐CD4 monoclonal antibodies, we determined that C. albicans Eno1 (CaEno1) primarily binds to the extracellular domain 3 of CD4. Functionally, we observed that CaEno1 binding to CD4 activated lymphocyte‐specific protein tyrosine kinase (LCK), which was also the case for anti‐CD4 monoclonal antibodies tested in parallel. CaEno1 binding to naïve human CD4 + T cells skewed cytokine secretion toward a Th2 profile indicative of poor fungal control. Moreover, CaEno1 inhibited human memory CD4 + T‐cell recall responses. Therapeutically, CD4 + T cells transduced with a p41/Crf1‐specific T‐cell receptor developed for adoptive T‐cell therapy were not inhibited by CaEno1 in vitro. Together, the interaction of human CD4 + T cells with CaEno1 modulated host CD4 + T‐cell responses in favor of the fungus. Thus, CaEno1 mediates not only immune evasion through its interference with complement regulators but also through the direct modulation of CD4 + T‐cell responses.