The cytokine TGF-β co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells

Abstract

Understanding the developmental mechanisms of T follicular helper (TFH) cells in humans is a highly relevant topic to clinic. However, factors that drive human CD4+ helper T (TH) cell differentiation program towards TFH cells remain largely undefined. Here we show that TGF-β provides critical additional signals for the transcription factors STAT3 and STAT4 to promote the initial TFH differentiation programs in humans. This mechanism does not appear to be shared with mouse TH cells. The developing human Bcl-6+ TFH cells also expressed RORγt, a transcription factor typically expressed by TH17 cells. Our study documents a mechanism by which TFH and TH17 cells co-emerge in inflammatory environments in humans, as often observed in many human autoimmune diseases.

Human T h 17 Cells Lack HIV-Inhibitory RNases and Are Highly Permissive to Productive HIV Infection

“…If IL-23 contributes to increased p24 production within T h 17 cells, the IL-23R-mediated activation of STAT3, which is activated in both T h 17 and T fh cells, should be further investigated for its potential role in promoting productive HIV infection (67). Such a finding would strengthen our argument that T h 17 and T fh differentiation (and unique activation pathways) are specifically linked to increased HIV permissiveness.…”

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…Together with IL-12 and IL-23, TGF-b is an important cofactor for the early differentiation of human Tfh cells in cell culture (Schmitt et al 2014). Interestingly, TGF-b signaling in mouse CD4 þ T cells was also shown to be required for Tfhcell development, although by using a different mechanism than what was shown in human cells.…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…However, although there is evidence that IL‐6 can also promote Tfh differentiation in humans,117 it is a not a good inducer of Bcl6 expression in human CD4 + T cells 118, 119. By contrast, human (but not murine) Tfh cell differentiation is potently induced by activin A120 and can also be driven by transforming growth factor β (TGFβ), particularly in combination with IL‐12 or IL‐23 121. Tfh differentiation is negatively regulated by other cytokines, including IL‐2122, 123 and IL‐7 124, 125…”

“…Bcl6 plays a central role in Tfh cell differentiation,115, 137, 138 but other transcription factors that act upstream and downstream of Bcl6 are also required (reviewed in 139). These include lymphoid enhancer‐binding factor 1 (LEF‐1) and T‐cell‐specific transcription factor 1 (TCF‐1), which act upstream of Bcl6 to promote Tfh cell differentiation140, 141, 142; basic leucine zipper transcription factor ATF‐like (Batf), which positively regulates Bcl6 and is important for IL‐4 expression143; interferon regulatory factor 4 (IRF4), which drives differentiation of IL‐12‐stimulated CD4 T cells to Tfh rather than Th1 cells144; achaete‐scute homolog 2 (Ascl2), which induces CXCR5 expression145; c‐Maf, which enhances expression of CXCR5, IL‐21, and IL‐4146; signal transducer and activator of transcription (STAT)s, STAT3 and 4 being particularly important for human Tfh cell differentiation and regulation of IL‐21 expression by human CD4 + T cells121, 147; and forkhead box protein O1 (FOXO1), which can both promote and inhibit Tfh cell differentiation 148. In addition, Tfh cell differentiation is regulated by microRNAs including members of the miRNA‐17‐92 family 149, 150.…”