CD4 T cells play a central role in orchestrating adaptive immune responses. After being activated through their T cell receptor (TCR) in a particular cytokine milieu, naive CD4 T cells differentiate into distinct T helper (Th) lineages, including Th1, Th2 and Th17 cells that produce interferon (IFN)-gamma, interleukin (IL)-4 and IL-17, respectively, as their signature effector cytokines. These cells are indispensable for different types of immunity to various microorganisms. Inappropriate Th responses to pathogens may lead to chronic infection and/or tissue damage to the host. Similarly, unnecessary activation of Th1, Th17 or Th2 cells by harmless environmental- or self-antigens can cause organ-specific autoimmune diseases or allergic inflammatory diseases. There are innate counterparts of Th cells. A class of innate lymphoid cells (ILCs), whose development requires signaling through the IL-2 receptor (IL-2R) common gamma chain and IL-7R alpha chain, has been recently discovered. Distinct subsets of ILCs are capable of producing similar sets of characteristic effector cytokines as produced by Th cells. Therefore, they are classified into type 1 innate lymphoid cells (ILC1s) that produce IFNg, type 2 innate lymphoid cells (ILC2s) that produce IL-5 and IL-13, and type 3 innate lymphoid cells (ILC3s) that produce IL-17 and IL-22. Within the ILC3s all of which express RORgt, there are two subsets -- CCR6+ (mainly lymphoid tissue inducers, LTis) and CCR6- ILC3s -- with the latter having the potential to develop into NKp46+ ILC3s that express both RORgt and T-bet. CCR6+ and NKp46+ ILC3s seem to have distinct biological functions and develop from different precursors. Like Th cells, ILCs are important for protective immune responses to infections and are responsible for the pathogenesis of many inflammatory diseases. Some ILCs such as LTis are critical for lymphoid organ development. The activation, differentiation and expansion of Th cells are tightly regulated by specific transcription factors. Among the lineage-specific transcription factors, T-bet, GATA3, RORgt and Foxp3 are deterministic for the differentiation of Th1, Th2, Th17 and Treg cells, respectively. These transcription factors have been referred as to master regulators. The differentiation of Th lineages is usually mutually exclusive, possibly due to the cross-regulation of the key transcription factors expressed by each lineage. However, many reports have indicated that the master regulator of one lineage may be expressed in other lineages. For example, among the Treg population, there are T-bet-expressing and GATA3-expressing Foxp3+ Treg cells. In addition, RORgt and T-bet co-expressing Th cells have been identified both in mice and in humans. How these master regulators function in a same cell is an intriguing question. The ILCs also express one or two or even three of the master regulators T-bet, GATA3 and RORgt, in a single cell level, and these factors are critical for the development and functions of ILC subsets. We have previously reported that T-bet and GATA3 are dynamically expressed by regulatory T cells and such dynamic expression is critical for maintaining immune tolerance (Nature Immunology, 16: 197-206, 2015). Single deletion of either Tbx21 or Gata3 gene specifically in Treg cells in mice did not result in an obvious phenotype in the steady state. However, the function of T-bet and GATA3 in Tregs during type 1 and/or type 2 immune responses is still unknown. During the past year, we have used T. gondii infection model (type 1) and OVA-induced airway allergic model (type 2) to address this question. Surprisingly, our results suggest that these Treg subsets may have a positive role during immune responses. We are currently investigating the mechanisms through which such positive effects of Tregs are executed. We have reported that GATA3 plays an essential role in the development of all IL-7Ra-expressing ILCs but not conventional NK cells (Immunity, 40: 378-88, 2014). This mirrors the essential function of GATA3 during CD4 but not CD8 T cell development indicating that NK cells may represent innate version of CD8 T cells and that GATA3 plays parallel roles in establishing and regulating both adaptive and innate lymphocyte subsets. During the past year, we further reported that despite its low expression level in mature ILC3s, GATA3 has important functions in regulating homeostasis, further maturation and functions of distinct ILC3 subsets (Nat. Immunol., 17:169-78, 2016). Using a novel GATA3 conditional-deficient mouse strain (Gata3fl/fl-Rorc-Cre) in which Gata3 is only deleted in cells that have expressed and/or are expressing RORgt, we found that three critical genes -- Il7r, Rorc and Il22 -- are regulated by GATA3 in ILC3s. Anti-GATA3 ChIP-Seq analysis indicates that all three genes are GATA3 direct targets in ILC3s. We also show that by promoting IL-7Ra expression, GATA3 regulates homeostasis of both CCR6+ and CCR6- ILC3 subsets; through its regulation of Il22 expression, GATA3 promotes ILC3-dependent protective immunity to Citrobacter rodentium infection; by fine-tuning RORgt expression and thus functional balance between T-bet and RORgt expression, GATA3 dictates the development of NKp46+ T-bet/RORgt co-expressing ILC3 subsets. In this study, we also compared global gene expression patterns between the CCR6+ and NKp46+ ILC3 subsets by using a novel T-bet-ZsGreen/RORgt-E2-Crimson dual reporter mouse strain that we have recently generated. Through RNA-Seq analysis of ILC3 subsets isolated from the dual reporter mice, we identified hundreds of CCR6+ and NKp46+ ILC3 lineage specific genes. Our unpublished data indicate that GATA3 may serve as a switch in determining the development of CCR6+ LTi cells versus other ILC lineages. In collaboration with Dr. Bing Sun's lab at the SIBCB in China, we report that a Th2 cell product, extracellular matrix protein 1 (ECM1), ameliorates the Th17 cell responses and EAE development in vivo (J. Immunol. 2016 Jun 17. pii: 1502457). ECM1 could interact with alphav integrin on dendritic cells and block the alphav integrin-mediated activation of latent TGF-beta, resulting in an inhibition of Th17 cell differentiation at an early stage of EAE induction. These results suggest that ECM1 may have the potential to be used in clinical applications for understanding the pathogenesis of MS.
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