The T helper cell (Th) paradigm has been used to explain how different adaptive immune responses are elicited in the host organism to clear infections with diverse microbial pathogens. Th17 cells, a newly defined subset of T helper cells, secrete signature cytokines interleukin (IL)-17, IL-17F, and IL-22. Th17 cells have been shown to play an important role in maintenance of mucosal integrity and immunity. On the other hand, disregulated Th17 responses result in autoimmunity both in mice and in humans. Another subset of CD4+ T cells, the regulatory T cells (Tregs), suppresses effector T cell responses and prevents their potentially pathogenic effects. It has been shown that the Forkhead transcription factor Foxp3 is required for Treg cell development and function. The differentiation of Th17 cells is induced by a combination of cytokines (IL-6 plus TGF-β) and requires transcription factor retinoid-related orphan receptor (ROR)γt. RORγt does not function in isolation, but coordinates the activity of a series of other essential transcription factors in guiding the differentiation of Th17 cells.
Recently, we and others showed that IL-6 induces IL-21 and the IL-23 receptor (IL-23R) in a sequential manner. IL-21 and IL-23 signaling, in concert with TGF-β, program naïve T cells into the Th17 lineage independently of IL-6. TGF-β has been well characterized as immunosuppressive, presumably through induction of subsets of Foxp3+ Treg cells that are capable of controlling effector T cell responses. Most recently, we have discovered that TGF-β orchestrates Th17 and Treg cell differentiation program in a concentration-dependent manner, through modulation of RORγt and Foxp3 balance and interaction.
Current research in our lab is focused on understanding 1) the molecular mechanisms of cytokine signaling pathways that lead to different T cell lineage fates. We are studying the roles of TGF-β and proinflammatory cytokines in Th17/Treg cell differentiation, focusing on the crosstalk between various cytokine signaling pathways; 2) the transcriptional networks of Th17 and Treg cell differentiation. We have identified multiple candidate transcription factors in the Th17 cell lineage through a series of gene profiling analyses. We are in the process of characterizing these factors in Th17 cell differentiation; and 3) the function of Th17 cells in autoimmunity and infection. We are generating novel mouse models to understand the role of various transcription factors in Th17 cell-mediated autoimmune diseases and pathogen infections.
Our lab employs a combination of molecular, biochemical, and mouse genetic approaches to dissect the signaling pathways and unravel the functions of various transcription factors in Th17 and Treg lineage determination. We believe that understanding the differentiation of Th17 and Treg cells at molecular levels will shed light on the regulation of the immune system and the pathogenesis of inflammatory diseases and may eventually provide novel means for treating human autoimmune and inflammatory diseases.
Selected Publications:
Zhou, L., Chong, M. M. W., Littman, D. R. Plasticity of CD4+ T cell lineage differentiation. Immunity. 30(5), 646-55 (2009).
Zhou, L., Littman, D. R. Transcriptional Regulatory Networks in TH17 Cell Differentiation. Curr. Opin. Immunol. 21(2), 146-52 (2009).
Zhou, L., Lopes, J., Chong, M. M. W., Ivanov, I. I., Min, R., Victora, G. D., Shen, Y., Du, J., Rubtsov, Y. P., Rudensky, A. Y., Ziegler, S. F., Littman, D. R. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature. 453 (7192), 236-40 (2008).
Zhou, L., Ivanov, I. I., Spolski, R., Min, R., Shenderov, K., Egawa, T., Levy, D. E., Leonard, W. J., Littman, D. R. IL-6 programs TH17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8 (9), 967-74 (2007).
Zhou, L., Nazarian, A. A., Xu, J., Tantin, D, Corcoran, L. M., Smale, S. T. An inducible enhancer required for Il12β promoter activity in an insulated chromatin environment. Mol. Cell. Biol. 27 (7), 2698-712 (2007).
Ivanov, I. I.*, McKenzie, B. S.*, Zhou. L. *, Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J., Littman, D. R. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 126 (6) 1121-33 (2006). *equal contributions
Zhou, L., Nazarian, A. A., Smale, S. T. Interleukin-10 inhibits interleukin-12 p40 gene transcription by targeting a late event in the activation pathway. Mol. Cell. Biol. 24 (6), 2385-96 (2004).
