Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells

Abstract

The cytokines controlling the development of human interleukin (IL) 17–producing T helper cells in vitro have been difficult to identify. 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 traits affecting transforming growth factor (TGF) β, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17–producing T cells. These data suggest that IL-12Rβ1– and STAT-3–dependent signals play a key role in the differentiation and/or expansion of human IL-17–producing T cell populations in vivo.

Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses

“…STAT3 is required for IL-17 and IL-22 secretion and likely contributes to IL-17-producing T-cell expansion and/or differentiation (25,(27)(28)(29). We, therefore, investigated STAT3 activation downstream of R381Q and WT IL23R in CD8+ T cells.…”

“…Given (13,25,26). STAT3 is required for IL-17 and IL-22 secretion and likely contributes to IL-17-producing T-cell expansion and/or differentiation (25,(27)(28)(29).…”

Induction, function and regulation of IL‐17‐producing T cells

“…These studies found that, unlike murine T cells, human naïve T cells did not differentiate into IL-17-secreting T cells in response to 50,52,53]. Furthermore, in a study of patients with genetic traits affecting TGF-b, IL-1, IL-6 and IL-23 production, enhanced TGF-b responses, due to mutations in TGFB1 and TGFBR2, did not alter expression of Th17 cells, whereas mutations in STAT3 and IL-12RB1 impaired dedifferentiation or expansion of Th17 cells in vivo [54].…”

“…These studies found that, unlike murine T cells, human naïve T cells did not differentiate into IL-17-secreting T cells in response to TGF-b and IL-6 in vitro [38,50,52,53]. Furthermore, in a study of patients with genetic traits affecting TGF-b, IL-1, IL-6 and IL-23 production, enhanced TGF-b responses, due to mutations in TGFB1 and TGFBR2, did not alter expression of Th17 cells, whereas mutations in STAT3 and IL-12RB1 impaired dedifferentiation or expansion of Th17 cells in vivo [54]. Three recent reports have demonstrated that TGF-b does have a role in promoting differentiation of human Th17 cells in vitro and that previous failures to identify a role for TGF-b reflected the high content of this cytokine in fetal bovine or human serum used to culture the T cells [53,55,56].…”

Severe infectious diseases of childhood as monogenic inborn errors of immunity

“…Unexpectedly, whereas investigations of MSMD led us to defects of Th1 cells, our studies of CMC led to the discovery of mutations in another arm of the effector CD4 + T-cell response, Th17 cells. Rare MSMD patients with IL-12 receptor β1 (IL-12Rβ1) deficiency who also displayed CMC bridged the two conditions (70). Patients with CMC display persistent or recurrent mucocutaneous infections with the commensal fungus Candida albicans.…”