Transforming growth factor-β induces development of the TH17 lineage

Abstract

A new lineage of effector CD4+ T cells characterized by production of interleukin (IL)-17, the T-helper-17 (T(H)17) lineage, was recently described based on developmental and functional features distinct from those of classical T(H)1 and T(H)2 lineages. Like T(H)1 and T(H)2, T(H)17 cells almost certainly evolved to provide adaptive immunity tailored to specific classes of pathogens, such as extracellular bacteria. Aberrant T(H)17 responses have been implicated in a growing list of autoimmune disorders. T(H)17 development has been linked to IL-23, an IL-12 cytokine family member that shares with IL-12 a common subunit, IL-12p40 (ref. 8). The IL-23 and IL-12 receptors also share a subunit, IL-12Rbeta1, that pairs with unique, inducible components, IL-23R and IL-12Rbeta2, to confer receptor responsiveness. Here we identify transforming growth factor-beta (TGF-beta) as a cytokine critical for commitment to T(H)17 development. TGF-beta acts to upregulate IL-23R expression, thereby conferring responsiveness to IL-23. Although dispensable for the development of IL-17-producing T cells in vitro and in vivo, IL-23 is required for host protection against a bacterial pathogen, Citrobacter rodentium. The action of TGF-beta on naive T cells is antagonized by interferon-gamma and IL-4, thus providing a mechanism for divergence of the T(H)1, T(H)2 and T(H)17 lineages.

TLR2‐activated human langerhans cells promote Th17 polarization via IL‐1β, TGF‐β and IL‐23

“…In our study TGF-b was found to be spontaneously released, independent of any agonist. By detection of IL-1b, IL-6, IL-23, and TGF-b we found cytokines that recently have been proposed to be crucial for Th17 commitment [15][16][17][18][19]. However, even in human T cells, IL-23 seems to be responsible rather for enhancement than commitment of IL-17 [34], but in human CD8 1 T cells also IL-17 induction was observed [35].…”

“…A panel of cytokines have been proposed for induction of Th17 development. In mice, TGF-b together with IL-6 [15], with IL-23 [16], or with IL-6 and TNF-a [17] were reported to drive the Th17 cell fate. In humans, IL-1b and IL-6 [18] or IL-23 and IL-1b [19] were observed to be crucial for Th17 commitment.…”

“…4C). Based on investigations showing Th17 polarization by adding differentiating cytokines in the absence of antigen-presenting cells [16][17][18][19], we examined whether IL-6 and TGF-b could enhance the secretion of IL-17 in CD4 1 T cells. Interestingly, supplement of external IL-6 and TGF-b to the cocultures reduced the potential to secrete IL-17 at stimulation by PGN, synthetic lipopeptides, and LPS in CD1c 1 MoLC and CD1c 1 MoDC (Fig.…”

T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

“…Th17 cells produce cytokines like IL-17, IL-22 and mediate immunity to extracellular bacteria and fungi, but are also responsible for autoimmunity and inflammation [12,13]. Development of naïve T cells to Th17 cells requires the presence of IL-6, TGF-b1 and the transcription factor RORgt [14][15][16][17]. [20,21].…”

A SNP uncoupling Mina expression from the TGFβ signaling pathway

“…Previously, we had shown that Mina is required for normal in vitro differentiation of T helper 17 (Th17) cells 4, an inflammatory CD4 T helper subtype with host protective roles in fungal and certain mucosal bacterial infections as well as pathological roles in pulmonary inflammation and autoimmune diseases including multiple sclerosis and rheumatoid arthritis 14, 22. The development of Th17 cells can be driven in vitro by a combination of interleukin‐6 (IL6) and TGFβ 23. To explore whether E2 contributed to Mina transcription during in vitro differentiation of Th17 cells, we used deep sequencing to enumerate Mina mRNA molecules transcribed from each parental allele in developing Th17 cells generated from [BALB/c × C57BL/6]F1 (CB6F1) mice.…”