Regulation of CD4⁺ T‐cell polarization by suppressor of cytokine signalling proteins

Abstract

Summary Suppressors of cytokine signalling (SOCS) proteins are induced in responses to many stimuli and by binding to cytokine receptors and associated janus kinase (JAK) proteins, directly regulate the activation of the signal transducers and activators of transcription (STATs). STAT proteins regulate the expression of many genes required for the differentiation of various CD4+ T helper cell lineages, and there is now accumulating evidence that SOCS also play essential roles in the regulation and maintenance of CD4+ T‐cell polarization. As it is now clear that CD4+ T cells are more plastic than initially thought, it is of particular importance to understand the molecular mechanisms regulating CD4+ T‐cell differentiation. Here we review the current understanding of how STATs and SOCS act in concert to influence the polarization of CD4+ T cells and highlight the relevance of this in disease.

Regulation of Foxp3+ Inducible Regulatory T Cell Stability by SOCS2

“…As reported by many studies, CD4 + lineages are not firmly committed as initially thought, but have some degree of plasticity, allowing coexpression of master transcriptional regulators and cytokines specific for other lineages (54). Interestingly, SOCS proteins seem to adjust the balance between the different CD4 + lineages (14). Indeed, SOCS1 and SOCS3 promote Th17 and Th2 differentiation, respectively, by inhibiting Th1 differentiation (15,18), whereas SOCS2 favors the development of Th17 cells at the expense of Th2 differentiation (16).…”

“…Recent studies implicate SOCS proteins as likely candidates to control differentiation of immune cells and thus help to shape the type of inflammatory response (12,13). Importantly, SOCS proteins appear to modulate CD4 + T cell polarization (14); this is exemplified by the differentiation of Th2 cells being regulated by SOCS3 and SOCS2 (15,16), whereas Th17 differentiation has been shown to be regulated by SOCS1 and SOCS3 (17,18).…”

Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3

“…Generally, T helper 1 (Th1) cell differentiation is mediated by the interferon-g (IFN-g)-STAT1 and interleukin-12 (IL-12)-STAT4 axis, Th2 differentiation by the IL-4-STAT6 axis, Th17 by the IL-6-STAT3 axis, and commitment to Treg pathway by the IL-2-STAT5 axis. 9,10 Consequently, mutations in STAT genes lead to variable clinical presentations, ranging from susceptibility to viral infections and mycobacterial disease to multiorgan autoimmunity. 2,[5][6][7][8] As an example, dominant-negative germline mutations in STAT3 cause hyperimmunoglobulin E (IgE) syndrome (HIES), 5,6 whereas recently discovered somatic activating STAT3 mutations have been found in 40% to 70% cases of large granular lymphocytic (LGL) leukemia, a neoplastic disease accompanied by autoimmune manifestations such as rheumatoid arthritis and autoimmune cytopenias.…”

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…With the identification of the T H 9 cell subset came the discovery that these cells can be converted from T H 2-polarized cells by treatment with transforming growth factor-β (TGFβ) 36 . 38 .…”