Abstract
A subset of CD4 + lymphocytes, regulatory T cells (Tregs), are necessary for central tolerance and function as suppressors of autoimmunity against self-antigens. The SRC-3 coactivator is an oncogene in multiple cancers and is capable of potentiating numerous transcription factors in a wide variety of cell types. Src-3 knockout mice display broad lymphoproliferation and hypersensitivity to systemic inflammation. Using publicly available bioinformatics data and directed cellular approaches, we show that SRC-3 also is highly enriched in Tregs in mice and humans. Human Tregs lose phenotypic characteristics when SRC-3 is depleted or pharmacologically inhibited, including failure of induction from resting T cells and loss of the ability to suppress proliferation of stimulated T cells. These data support a model for SRC-3 as a coactivator that actively participates in protection from autoimmunity and may support immune evasion of cancers by contributing to the biology of Tregs.
Highlights
SRC-3 functions as a transcriptional coactivator for steroid hormone receptors including the estrogen, progesterone and numerous other nuclear receptors, and functions as a primary coactivator for many other DNAbinding transcription factors including E2F, NFκB, and members of the ETS family[1,2,3,4]
Since transcriptional regulation in Tregs is critical for cell type lineation, identity, and function, we considered that the observed enrichment of the SRC-3 transcriptional coactivator could influence expression of typical Treg marker genes
We consistently observed significantly reduced numbers of FOXP3 + /CD25 + cells when SRC-3 was inhibited during Induction of Tregs (iTregs) induction of resting CD4 cells (Fig. 3B) from nine healthy donors spanning a broad range of age and genders (See Supplementary Fig. 3B online)
Summary
SRC-3 functions as a transcriptional coactivator for steroid hormone receptors including the estrogen, progesterone and numerous other nuclear receptors, and functions as a primary coactivator for many other DNAbinding transcription factors including E2F, NFκB, and members of the ETS family[1,2,3,4]. SRC-3 can be extensively modified by post-translational modifications (PTMs), including phosphorylation, methylation, acetylation, and ubiquitination that regulate its function and affinity for transcription factors and coactivator protein complexes[5,6]. These combinatorial PTMs are reflective of the environment of hormones, cytokines, and environment to which cells are exposed and the state of their respective signaling pathways. Various suppressive immune cell types from myeloid or lymphoid origins are known to block anti-tumor immunity, including myeloid-derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), and regulatory T cells (Tregs) The latter cell type is of particular interest since Treg infiltration has been experimentally proven in breast tumor biopsies and correlates with poor prognosis and reduced breast cancer patient survival[7,8]. Regulation of the FOXP3 gene is a critical determinant for immune self-tolerance, and factors controlling FOXP3 transcription may be attractive targets to modulate Treg activity
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