Regulation of innate-like CD4 T cell development and function
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 thymic epithelial cell (TEC) 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 thymocyte-driven pathway of CD4 T cell selection. Thus, both epithelial cells and thymocytes support human CD4 T cell development and, as a consequence, two CD4 T cell populations coexist in humans.
We showed that thymocyte-selected CD4 (T-CD4) T cells but not epithelial cell-selected CD4 (E-CD4) T cells produce both Th1 and Th2 cytokines immediately after stimulation, suggesting that they could be potent helper T cells. In addition, T-CD4 T cells do not require Stat6 to express the IL-4 gene and the IL-4 locus is already remodeled upon positive selection suggesting that T-CD4 T cells have received distinct signals by thymocyte-thymocyte interaction during selection. Surprisingly, T-CD4 T cells inhibit the generation of effector CD4 T cells or memory CD8 T cells upon Helicobacter pylori or Listeria monocytogenes infection, respectively. Unlike E-CD4 T cells, CD25-Foxp3- T-CD4 T cells suppress immune responses mediated by CD4 and CD8 T cells. Taken all together, T-CD4 T cells represent a unique T cell population and understanding of their development and function bears high significance.
Currently, 3 different projects are ongoing all of which address T-CD4 T cell development and function.
Li, W., M. H. Sofi, N. Yeh, S. Sehra, B. P. McCarthy, D. R. Patel, R. R. Brutkiewicz, M. H. Kaplan, and C.-H. Chang. 2007. Thymic selection pathway regulates the effector function of CD4 T cells. J. Exp. Med. 204:2145. (Highlighted by the JEM and Nat Imm Rev).
Li, W., H. Sofi, S. Rietdijk, N. Wanag, C. Terhorst and C.-H. Chang. 2007. The SLAM-Associated Protein Signaling Pathway Is Required for Development of CD4+ T Cells Selected by Homotypic Thymocyte Interaction. Immunity 27:763–774 (Highlighted by Nat Imm Rev)
M. Hanief Sofi, Zhiping Liu, Lingqiao Zhu, Qiao Yu, Mark H. Kaplan and Cheong-Hee Chang. Regulation of IL-17 expression by the developmental pathway of CD4 T cells in the thymus. Mol. Immunol. 2010. 47:1262-1268.
M. Hanief Sofi, Yu Qiao, K. Mark Ansel, Masato Kubo, Cheong-Hee Chang. Induction and maintenance of IL-4 expression are regulated differently by the 3’enhancer in CD4 T cells. J. Immunol. 2011. 186: 2792-2799
Yu Qiao, B. M. Gray, M. H. Sofi, Laura D. Bauler, and K. A. Eaton, Mary X. D. O’Riordan, and Cheong-Hee Chang. Innate-like CD4 T cells selected by thymocytes suppress adaptive immune responses against bacteria infections. Open J. Immunol. 2012. 2:25-39.
JiHoon Chang, Laurence A. Turka and Cheong-Hee Chang. MyD88 is essential to sustain mTOR activation necessary to promote Th17 cell proliferation by linking IL-1 and IL-23 signaling. PNAS. In revision.
Y. Qiao, L. Zhu, H. Sofi, P. E. Lapinski, R. Horai, K. Mueller, G. L. Stritesky, X. He, H-S Teh, D. 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. In revision
Lingqiao Zhu, Esther Choi, Joy Das, Derek B. Sant’Angelo, and Cheong-Hee Chang. A transgenic TCR instructs the development of IL-4+ and PLZF+ innate CD4 T cells by thymocytes. Submitted