The Current STATus of lymphocyte signaling: new roles for old players

Abstract

Recently, our understanding of helper/effector T cell differentiation has changed significantly. New subsets of T cells continue to be recognized, including Th17, Treg, and Th9 cells. In addition, the signaling pathways that contribute to their generation continue to be refined. It has become clear that STAT family proteins play a major role in these 'new' T cell fates, along with their critical role in more classical fates. Importantly, genetic studies implicate STATs in autoimmune and primary immunodeficiency diseases in humans. Focusing on how STATs work in concert with other transcription factors will hopefully provide a better mechanistic understanding of the pathogenesis of various autoimmune diseases.

Figure 1

CD4 T cell differentiation is critical in host defense. Following engagement of the T cell receptor, cytokines shape T cell commitment to various fates including Th1, Th2, Th9, Th17 and Treg cells. The important cytokines, their receptors, and specific STAT transcription factors that contribute to this intricate differentiation process are shown. In the case of Th1 cells, IL-12 drives naïve CD4+ cells to produce INF-γ. Other recently identified STAT4 target genes include Hlx, Map3k8 and Furin. Tregs develop from naïve T-cells in the presence of TGF-β and IL-2. Signaling through STAT5 results in the up-regulation of the transcription factor FOXP3, which also suppresses Th17 differentiation. Tregs play an important role in peripheral self-tolerance and immune suppression and secrete several cytokines including IL-10, IL-35, and TGF-β. Th17 cells develop from naïve CD4+ T cells through stimulation via IL-6 and TGF-β. The former activates STAT3, enhancing expression of the transcription factors RORγt and RORα, which in cooperation with the Arylhydrocarbon receptor promote expression of unique Th17 cytokine products: IL-17A, IL-17F, IL-21 and IL-22. Mutations of STAT3 underlie the human primary immunodeficiency syndrome hyperIgE or Job’s syndrome. Th17 cells are involved in promoting inflammation and host defense against certain infectious agents. Activation of STAT1, STAT5, and STAT6 inhibit IL-17 production. Similarly, retinoic acid (RA) inhibits IL-17 but promotes Foxp3 expression.