Enolase 1 of Candida albicans binds human CD4 and modulates both naïve and memory T cell responses
DAUD M. 1, DASARI P. 2, ADELFINGER M. 3, LANGENHORST D. 1, LOTHER J. 3, SLAVKOVIC-LUKIC D. 3, BERGES C. 3, KRUHM M. 3, GALLER A. 4, SCHLEUSSNER C. 4, H. LUTHER C. 5, ALBERTER K. 1, ALTHAMMER A. 1, SHAIKH H. 3, PALLMANN N. 1, BODEM J. 1, ELMOWAFY M. 1,6, BEILHACK A. 3, DITTRICH M. 5,7, S. TOPP M. 3, ZIPFLER P. 2,8, BEYERSDORF N. 1
1 University of Wuerzburg, Würzburg, Germany; 2 Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany; 3 University Hospital Würzburg, Department of Internal Medicine II, Division of Hematology, Würzburg, Germany; 4 T-Balance Therapeutics, Frankfurt, Germany; 5 University of Würzburg, Chair of Bioinformatics, Würzburg, Germany; 6 Mansoura University, Faculty of Pharmacy, Department of Microbiology & Immunology, Mansoura, Egypt; 7 University of Würzburg, Institute of Human Genetics, Würzburg, Germany; 8 Friedrich Schiller University, Jena, Germany
Recently, we conducted an in silico screening for fungal and host protein interaction partners to obtain a better understanding of the infection biology of life-threatening fungal infections caused by Candida albicans. 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 (mAb) we determined that the extracellular domain 3 of CD4 is involved in C. albicans Eno1 (CaEno1) binding. Binding of CaEno1 to CD4 activated LCK, which was also the case for anti-CD4 mAb tested in parallel. At the cellular level, CaEno1 binding to naïve human CD4+ T cells skewed cytokine secretion towards a Th2 profile associated with poor fungal control. Moreover, CaEno1 inhibited human memory CD4+ T cell recall responses. This was, however, not the case for CD4+ T cells transduced with a p41/Crf-1-specific TCR developed for adoptive T cell therapy of both invasive candidiasis as well as aspergillosis. Together, interaction of human CD4+ T cells with CaEno1 modulated host CD4+ T cell responses in favor of the fungus. Thus, CaEno1 not only mediates immune evasion through its interference with complement regulators, but also through direct modulation of CD4+ T cell responses.