Differential regulation of lineage-determining transcription factor expression in innate lymphoid cell and adaptive T helper cell subsets

Abstract

CD4 T helper (Th) cell subsets, including Th1, Th2 and Th17 cells, and their innate counterparts innate lymphoid cell (ILC) subsets consisting of ILC1s, ILC2s and ILC3s, display similar effector cytokine-producing capabilities during pro-inflammatory immune responses. These lymphoid cell subsets utilize the same set of lineage-determining transcription factors (LDTFs) for their differentiation, development and functions. The distinct ontogeny and developmental niches between Th cells and ILCs indicate that they may adopt different external signals for the induction of LDTF during lineage commitment. Increasing evidence demonstrates that many conserved cis-regulatory elements at the gene loci of LDTFs are often preferentially utilized for the induction of LDTF expression during Th cell differentiation and ILC development at different stages. In this review, we discuss the functions of lineage-related cis-regulatory elements in inducing T-bet, GATA3 or RORγt expression based on the genetic evidence provided in recent publications. We also review and compare the upstream signals involved in LDTF induction in Th cells and ILCs both in vitro and in vivo. Finally, we discuss the possible mechanisms and physiological importance of regulating LDTF dynamic expression during ILC development and activation.

Thymic dendritic cell-derived IL-27p28 promotes the establishment of functional bias against IFN-γ production in newly generated CD4+T cells through STAT1-related epigenetic mechanisms

“…Next, we investigated the expression of T-box transcription factor (T-bet) and GATA3, which are the master regulators of Th1 and Th2 differentiation, respectively ( Fang et al, 2022 ). The differential impact of IL-27p28 deficiency on IFN-γ and IL-4 production was accompanied by an increase in Tbx21 expression but no significant alteration in Gata3 expression (Figure 1D).…”

“…In other reports, Th2 polarization in adult SP thymocytes and RTEs is attributable to active recruitment of DNA methyltransferases and increased H3K4 methylation at Il4 locus ( Berkley et al, 2013; Makar et al, 2003 ). In addition, DNA methylation and histone modification are found to be important for the control of Ifng and Tbx21 expression (Fang et al, 2022; Friedman et al, 2023; Jones & Chen, 2006) . Therefore, we next evaluated the contribution of epigenetic modifications to the enhanced IFN-γ production in the absence of IL-27p28.…”

The DC–T cell axis is an effective target for the treatment of non‐small cell lung cancer

“…Under the influence of antigens presented by DCs, CD4 + naive T cells (CD4 + Tn) can differentiate into CD4 + T cells. T helper 1 (Th1), Th2, Th17, and regulatory T (Treg) cells have extensively been studied within this subset 25,27,28 …”

“…T helper 1 (Th1), Th2, Th17, and regulatory T (Treg) cells have extensively been studied within this subset. 25,27,28 Th1 primarily secretes interleukin-2 (IL-2), IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), which facilitates Th1 proliferation and regulates cellular immunity. In addition, these cytokines inhibit Th2 proliferation.…”

ITK signaling regulates a switch between T helper 17 and T regulatory cell lineages via a calcium-mediated pathway

“…Commitment of naïve CD4 + T cells to generally pro-inflammatory Th17 effector fates, or to generally anti-inflammatory Foxp3 + Treg fates, have been shown to be dependent on the strength of TCR signaling and the cytokines present in the microenvironment (2)(3)(4)(5)(6). Key events include triggering of TCR upon interaction with antigen/MHC complexes and subsequent recruitment of the Src family of kinases Lck/Fyn, and Syk family of kinase ZAP-70 (zeta chain associated kinase), which phosphorylates adaptor proteins LAT (linker for activation of T cell) and SLP76 (SH3 containing lymphocyte protein) (7,8).…”