The IL-12-IFN-γ axis plays an important role in the immunity against mycobacteria. I have identified and studied a cohort of patients with a complete autosomal recessive IL12RB1 deficiency coding for the β1 subunit of the IL-12 and IL-23 receptors. We herein report an international survey of 137 patients from 101 kindreds and 30 countries. A total of 52 IL12RB1 mutant alleles were found. All patients had a functional complete IL-12Rβ1 deficiency, most with a lack of IL-12Rβ1 expression at the cell surface. Clinical phenotypes are heterogeneous from an absence of infection to the death following infection. In most cases, infection consisted in mycobacterial diseases (BCG, environmental mycobacteria and tuberculosis) and/or salmonella diseases. Candidiasis was also being frequently associated to this defect. The IL-23-IL-17 axis seems to play a role in the differentiation and activation of the Th17 CD4+ T cells. The cytokines controlling the development of these cells are not well known. We addressed the question of the development of human IL-17-producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic disorders affecting TGF-β (patients TGFB1, TGFBR1 and TGFBR2), IL-1β (patients IRAK4 and MYD88), IL-6 (patients STAT3), or IL-23 (patients IL12B and IL12RB1) responses. Mutations in STAT3 and, to a lesser extent mutations in IL12B and IL12RB1, impaired the development of IL-17- producing T cells. These data suggest that these molecules play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo
