C DE GREGORIO¹, S BECATTINI¹, J BUSTAMANTE², JL CASANOVA³, A PUEL², F SALLUSTO<sup>1

1</sup>Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland, ²Institut Imagine, Paris, France, ³The Rockefeller University, New York, USA

CD4+ Th cells are crucial players in the adaptive immune response against microbial pathogens. Th1 cells secrete IFN- and activate immunity to intracellular pathogens, Th2 cells secrete IL-4, IL-5 and IL-13 and are essential against extracellular parasites, while Th17 cells secrete IL-17A and IL-22 and protect from fungal pathogens such as Candida albicans. We developed a high throughput cell based assay that, combined with sorting of T cell subsets and with in vitro priming assays, can provide new insights on the class and specificity of the human T cell response to pathogens. With this approach we recently demonstrated that in healthy donors memory T cells specific for C. albicans are present at high frequency in CCR6+ Th17 and Th1* subsets and at low frequency in CCR6– Th1 and Th2 subsets (1). Using next generation TCR Vβ sequencing, we also demonstrated that several clonotypes were present in more than one subset and, in some cases, in all subsets, unraveling an unexpected degree of intraclonal functional heterogeneity of the human T cell response to pathogens. To understand the role of different T cell subsets in host protection, we are now studying the repertoire (class, frequency, and clonotypic composition) of C. albicans-specific T cells in patients with primary immunodeficiencies suffering of chronic mucocutaneous candidiasis (CMC). Patients with STAT1 gain-of-function mutations (STAT1-GOF) showed an altered distribution of C. albicans-specific T cells in memory subsets, with a high frequency of cells present in the CCR6– Th1 and Th2 subsets and a few present in the CCR6+ Th17 and Th1* subsets. Currently, we are analyzing patients with STAT3 loss-of-function mutations (STAT3-LOF) and patients with other primary immunodeficiencies (IL-17RA-deficiency, ACT1-deficiency). These studies are expected to improve our knowledge about disease pathogenesis and may be useful for the design of novel immunotherapeutic strategies.

1. Becattini S et al., Science 2015; 347:400