Steroid receptor coactivators in Treg and Th17 cell biology and function

Abstract

Steroid receptor coactivators (SRCs) are master regulators of transcription that play key roles in human physiology and pathology. SRCs are particularly important for the regulation of the immune system with major roles in lymphocyte fate determination and function, macrophage activity, regulation of nuclear factor κB (NF-κB) transcriptional activity and other immune system biology. The three members of the p160 SRC family comprise a network of immune-regulatory proteins that can function independently or act in synergy with each other, and compensate for - or moderate - the activity of other SRCs. Recent evidence indicates that the SRCs are key participants in governing numerous aspects of CD4⁺ T cell biology. Here we review findings that establish the SRCs as essential regulators of regulatory T cells (Tregs) and T helper 17 (Th17) cells, with a focus on their crucial roles in Treg immunity in cancer and Treg-Th17 cell phenotypic plasticity.

Keywords: Th17 cells; Treg cells; cell therapy; nuclear coactivators (NCoAs); steroid receptor coactivators (SRCs).

Figure 1

SRCs as regulators of Treg biology. (A) SRC-2 and SRC-3 are important regulators of Treg activity: SRC-2 is a transcriptional upregulator of Nr4a2 – a positive TF of Tregs, which makes SRC-2 indispensable for Treg differentiation and suppression of autoimmunity (left). SRC-3 is important for the immunosuppressive activity of Tregs and the inhibition of its activity abolishes the ability of CD4⁺ T cells to acquire a suppressive phenotype (middle and right). (B) SRC-3 controls the suppressive activity of Tregs in the TME: Presence of SRC-3 KO FOXP3⁺ T cells reshapes the TME in a way that leads to tumor eradication in breast and prostate cancer mice models.

Figure 2

SRCs as regulators of Th17 cells. (A) Two possible mechanisms by which SRC-1 contributes to Th17 differentiation and phenotype dominance over Tregs: 1) PKCθ-driven phosphorylation of SRC-1 enhances its interaction with RORγt, which results in dominance of RORγt over FOXP3 transcriptional activity. 2) The SRC-1-RORγt complex promotes the recruitment of CARM1 to the IL-17 locus to generate a permissive chromatin structure that leads to enhanced transcription of the IL17A gene. (B) SRC-3 regulates the expression of genes in Th17 cells through the IL-1 mediated signaling axis: Under stimulation with IL-1/6/23, a RORγt-SRC-3 complex is recruited to the promoters of the IL17A and IL17R1 genes to induce their expression, resulting in the polarization of naïve CD4⁺ T cells into the Th17 cell lineage.