Genetic controls of Th17 cell differentiation and plasticity

Abstract

CD4+ T lymphocytes play a major role in regulation of adaptive immunity. Upon activation, naïve T cells differentiate into different functional subsets. In addition to the classical Th1 and Th2 cells, several novel effector T cell subsets have been recently identified, including Th17 cells. There has been rapid progress in characterizing the development and function of Th17 cells. Here I summarize and discuss on the genetic controls of their differentiation and emerging evidence on their plasticity. This information may benefit understanding and treating immune diseases. Keywords: CD4-positive T-lymphocytes; cell differentiation; cytokines; Th17 cells; transcription factorsAfter activation by antigen-presenting cells (APC), naïve, antigen-specific CD4 + T cells differentiate into effector T cells. Two decades ago, Coffman and Mosman first discovered the heterogeneity of effector T cells, which were then named as Th1 or Th2 cells (Mosmann and Coffman, 1989). Th1 and Th2 cells are differentially induced and regulate immunity against intracellular and extracellular pathogens, respectively, as well as immunopathologies such as autoimmunity and allergy. The Th1/Th2 dichotomy has dominated the field of immune regulation until five years ago when IL-17-expressing T cells were proposed to be a third lineage of helper T cells (Harrington et al., 2005;Park et al., 2005). In addition to these so-called Th17 cells, additional T cell subsets were also discovered or studied, including T follicular helper (Tfh) cells and IL-9-expressing "Th9" cells, etc.Th cell differentiation is instructed by distinct environmental cytokines, which signals through STAT or other inducible but generally ubiquitous transcription factors. These factors then upregulate the expression of lineage-specific transcription factors, which function not only to promote its own lineage differentiation but also to inhibit the alternate differentiation pathways. There are extensive cross-regulations of lineage-determining transcription factors. Moreover, there is growing evidence that Th cell lineage commitment can be plastic in certain circumstances. Here, I summarize our current understanding on the genetic controls of Th17 cell lineage differentiation and discuss on the evidence and mechanisms underlying their plasticity.

Higher infiltration by Th17 cells compared with regulatory T cells is associated with severe acute T-cell-mediated graft rejection

“…(Dong, 2011). Of note, the Th17 cell developed from a common precursor with the FOXP3 + Treg (Awasthi et al, 2008;Weaver and Hatton, 2009).…”

Cytokines in Systemic Sclerosis: Focus on IL-17

“…However IL-23 is not required for the differentiation of Th17 from naïve CD4 T cells. Several transcription factors have been shown as critical regulators of Th17 cell differentiation (Dong 2011). STAT3 has been reported to be a crucial component of IL-6 and IL-21-mediated Th17-cell regulation.…”

“…Other transcription factors such as the aryl hydrocarbon receptor (AHR), Batf (member of AP-1 transcription factor family), IκBζ (encoded by the Nfkbiz gene) have recently been shown to be required for Th17 cell development (Dong 2011). Differentiation of Th17 and regulatory T cells, both of which depend on TGF-, shares a reciprocal regulation.…”

Parasitic Helminths as Potential Therapeutic Agents Against Autoimmune Disorders

“…Complicating the situation further is the recent finding that Th17 is not a stable subset and can be changed to the Th1 phenotype; i.e. plasticity of Th17 (Kurschus et al, 2010;Dong, 2011). The fate of Th17 cells depends on their surrounding environment (Dong, 2011;Lee et al, 2009) and Th17's pathogenic nature depends on the conversion to Th1 cells, in the case of experimental T1D (Martin-Orozco et al, 2009;Bending et al, 2009).…”

“…plasticity of Th17 (Kurschus et al, 2010;Dong, 2011). The fate of Th17 cells depends on their surrounding environment (Dong, 2011;Lee et al, 2009) and Th17's pathogenic nature depends on the conversion to Th1 cells, in the case of experimental T1D (Martin-Orozco et al, 2009;Bending et al, 2009). The relative importance of each Th subset to the pathogenesis may differ with the disease model, however in most cases, the pathogenicity of Th1 and Th17 is still under debate.…”