Studies of molecular and cellular mechanisms for T cell-mediated immunity
The research program in my laboratory has been focusing on investigating and understanding the molecular mechanisms that govern the adaptive immune function. In particular, we are studying CD4 T cell development and effector functions.
It is well accepted that the immune system of humans is similar to that of mouse and therefore mouse models are commonly used to study immune responses and diseases. However, the two exhibit differences in CD4 T cell development. Conventional understanding of CD4 T cell development is that the MHC class II molecules on cortical epithelial cells are necessary for selection, as shown in mouse models. Clinical data, however, show that hematopoietic stem cells reconstitute CD4 T cells in patients devoid of MHC class II. The difference observed in humans can be explained by our discovery that the CD4 compartment is efficiently reconstituted by MHC class II expressing thymocytes, demonstrating a novel hematopoietic cell-driven pathway of CD4 T cell selection. Thus, both epithelial cells and hematopoietic cells support human CD4 T cell development and, as a consequence, two CD4 T cell populations coexist in humans.
Because hematopoietic-selected CD4 T cells exhibit the innate-like phenotype, we named them innate CD4 (iCD4) T cells. Unlike epithelial cell-selected conventional CD4 (cCD4) T cells, iCD4 T cells produce both Th1 and Th2 cytokines immediately after stimulation and exhibit a regulatory function. iCD4 T cells also show unique requirements of signaling for their metabolism which controls immune diseases. With these observations we are investigating two areas: (i) molecular mechanisms by which iCD4 T cells develop and function in both mouse and human, and (ii) their role in inflammation, immunodeficiency, and cancer.
Yao, Y., W. Li, M. Kaplan and C-H Chang. IL-4 inhibits IL-10 to promote IL-12 production by dendritic cells. 2005. J. Exp. Med. 201:1899-1903. Highlighted in the same issue of JEM.
Li, W., H. Sofi, N. Yeh, D. Patel, R. Brutkiewicz, M. Kaplan, and C-H Chang. Thymic selection pathway regulates cytokine production potential of CD4 T cells. 2007. J. Exp Med. 204:2145 (Highlighted in J. Exp. Med. and Nat. Immunol. Rev) PMCID: PMC2118694
Li, W., H. Sofi, S. Rietdijk, N. Wanag, C. Terhorst and C-H Chang. The SLAM-associated protein signaling pathway is required for development of CD4 T cells selected by homotypic thymocyte interaction. 2007. Immunity. 27:763-774. (Highlighted by Nat. Immunol Rev.) PMCID: PMC2757291
Qiao, T., L. Zhu, H. Sofi, P.E. Lapinski, R. Horai, K. Mueller, G.L. Stritesky, X. He, H. Teh, D.L. Wiest, D.J. Kappes, P.D. King, K.A. Hogquist, P.L. Schwartzberg, D.B. Sant’Angelo, and C-H Chang. Development of PLZF expressing innate CD4 T cells require stronger T cell receptor signals than conventional CD4 T cells. PNAS. 2012. 109: 16264–16269. PMCID:PMC3479572
Chang, J., L.A. Turka and C-H Chang. MyD88 is essential to sustain mTOR activation necessary to promote Th17 cell proliferation by linking IL-1 and IL-23 signaling. PNAS. 2013. 110:2270-5. PMCID:PMC3568327
Zhu, L., Y. Qiao, E. S. Choi, J. Das, D.B. Sant’Angelo, and C-H Chang. A transgenic TCR directs the development of IL-4+ and PLZF+ innate CD4 T cells. J. Immunol. 2013. 191:737-44. PMCID:PMC3702648 (Highlighted in “In this issue” of J. Immunology)
Chang, J., L.A. Turka and C-H Chang. MyD88 is essential to sustain mTOR activation necessary to promote Th17 cell proliferation by linking IL-1 and IL-23 signaling. PNAS. 2014. 110:2270-5. PMCID:PMC3568327
Prevot, N., K. Pyaram, E. Bischoff, J. M. Sen, J. D. Powell, C-H Chang. Mammalian target of Rapamycin Complex 2 Regulates Invariant Natural Killer T Cell Development and Function Independent of Promyelocytic Leukemia Zinc-finger. J Immunol. 2015. 194:223-30.