The immune system plays a critical role in protecting hosts from the invasion of organisms. CD4 T cells, as a key component of the immune system, are central in orchestrating adaptive immune responses. After decades of investigation, five major CD4 T helper cell (Th) subsets have been identified: Th1, Th2, Th17, Treg (T regulatory), and Tfh (follicular T helper) cells. Th1 cells, defined by the expression of lineage cytokine interferon (IFN)-γ and the master transcription factor T-bet, participate in type 1 immune responses to intracellular pathogens such as mycobacterial species and viruses; Th2 cells, defined by the expression of lineage cytokines interleukin (IL)-4/IL-5/IL-13 and the master transcription factor GAΤA3, participate in type 2 immune responses to larger extracellular pathogens such as helminths; Th17 cells, defined by the expression of lineage cytokines IL-17/IL-22 and the master transcription factor RORγt, participate in type 3 immune responses to extracellular pathogens including some bacteria and fungi; Tfh cells, by producing IL-21 and expressing Bcl6, help B cells produce corresponding antibodies; whereas Foxp3-expressing Treg cells, unlike Th1/Th2/Th17/Tfh exerting their effector functions, regulate immune responses to maintain immune cell homeostasis and prevent immunopathology. Interestingly, innate lymphoid cells (ILCs) have been found to mimic the functions of three major effector CD4 T helper subsets (Th1, Th2, and Th17) and thus can also be divided into three major subsets: ILC1s, ILC2s, and ILC3s. In this review, we will discuss the differentiation and functions of each CD4 T helper cell subset in the context of ILCs and human diseases associated with the dysregulation of these lymphocyte subsets particularly caused by monogenic mutations.
T-bet-expressing Th17 (T-bet+RORγt+) cells are associated with the induction of pathology during experimental autoimmune encephalomyelitis (EAE) and the encephalitic nature of these Th17 cells can be explained by their ability to produce GM-CSF. However, the upstream regulatory mechanisms that control Csf2 (gene encoding GM-CSF) expression are still unclear. In this study, we found that Th17 cells dynamically expressed GATA3, the master transcription factor for Th2 cell differentiation, during their differentiation both in vitro and in vivo. Early deletion of Gata3 in three complimentary conditional knockout models by Cre-ERT2, hCd2Cre and Tbx21Cre, respectively, limited the pathogenicity of Th17 cells during EAE, which was correlated with a defect in generating pathogenic T-bet-expressing Th17 cells. These results indicate that early GATA3-dependent gene regulation is critically required to generate a de novo encephalitogenic Th17 response. Furthermore, a late deletion of Gata3 via Cre-ERT2 in the adoptive transfer EAE model resulted in a cell intrinsic failure to induce EAE symptoms which was correlated with a substantial reduction in GM-CSF production without affecting the generation and/or maintenance of T-bet-expressing Th17 cells. RNA-Seq analysis of Gata3-sufficient and Gata3-deficient CNS-infiltrating CD4+ effector T cells from mixed congenic co-transfer recipient mice revealed an important, cell-intrinsic, function of GATA3 in regulating the expression of Egr2, Bhlhe40, and Csf2. Thus, our data highlights a novel role for GATA3 in promoting and maintaining the pathogenicity of T-bet-expressing Th17 cells in EAE, via putative regulation of Egr2, Bhlhe40, and GM-CSF expression.
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