P53

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

Abstract
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.