Text Image: UM Medical School: Graduate Program in Immunology
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Cheong-Hee Chang, Ph.D.
Microbiology and Immunology

Current Research Activity

Regulation of innate 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 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. In addition, iCD4 T cells inhibit the generation of effector CD4 T cells or memory CD8 T cells upon Helicobacter pylori or Listeria monocytogenes infection, respectively. Taken all together, iCD4 T cells represent a unique T cell population, and understanding of their development and function bears high significance. Currently, two main projects are ongoing all of which address iCD4 T cell development and function.

(1) Study of signaling pathways that regulate iCD4 T cell selection, which in turn controls the function

(2) Investigation of human iCD4 T cells for their function during immune responses

Selected Publications

Li, W., M. G. Kim, T. S. Gourley, D. Sant'Angelo, and C.-H. Chang. 2005. An Alternate Pathway for CD4 T cell Development: Thymocyte-Expressed MHC Class II Selects a Distinct T cell Population.  Immunity. 23:375.

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)

JiHoon Chang, Steven Kunkel and Cheong-Hee Chang. Negative regulation of MyD88-dependent signaling by Interleukin-10 in dendritic cells. PNAS.2009. 106:18327-32

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.

Yu Qiao, Lingqiao Zhu, Hanief Sofi, Philip E. Lapinski, Reiko Horai, Kristen Mueller, Gretta L. Stritesky, Xi He, Hung-Sia Teh, David L. Wiest, Dietmar J. Kappes, Philip D. King, Kristin A. Hogquist, Pamela L. Schwartzberg, Derek B. Sant’Angelo, and Cheong-Hee 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

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. 2013. 110:2270-5

Lingqiao Zhu, Yu Qiao, Esther S. Choi, Joy Das, Derek B. Sant’Angelo, and Cheong-Hee Chang. A transgenic TCR directs the development of IL-4+ and PLZF+ innate CD4 T cells. J Immunol. 2013. 191:737-44. (Highlighted in “In this issue” of J. Immunology)

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