Th17 cells, pathogenic or not? TGF-β3 imposes the embargo

Nearly 100 individuals have been identified who carry deleterious biallelic germline variants in CARD9 and experience life-threatening, invasive fungal infections caused by Ascomycetes but are otherwise resistant to other infectious agents. CARD9 is an adaptor protein expressed predominantly in myeloid cells, which functions downstream of dectin receptors, pattern recognition receptors for fungal antigens, to activate innate immune responses. The impact of CARD9 deficiency on lymphocytes, however, is less clear. We deciphered the functional consequences and delineated mechanisms of disease in a patient (P1) with a nonsense germline homozygous CARD9 variant (c.673A>T/p.K225*) and invasive Candida disease. P1's PBMCs expressed truncated CARD9 and showed significantly reduced cytokine production in response to fungal ligands. P1 had reduced frequencies of circulating memory CD4+ TH17-like (CCR6+CXCR3-) cells. In addition, in vitro differentiation of P1's naive CD4+ T cells into IL-17A/IL-17F-secreting cells was greatly impaired. Consistent with impaired responses of innate and adaptive immune cells from P1 in vitro, proportions of Candida-specific CD4+ T cells were strongly and selectively diminished. Our findings suggest that the CARD9 variant identified in P1 is pathogenic, affecting not only CARD9-induced immunity mediated by myeloid cells but also CD4+ T cell-intrinsic IL-17-dependent immunity and Candida-specific T cell responses.