Primary Academic Appointment:
  Dept. of Microbiology and Immunology

Center Affiliation:
  Center for Vaccine Biology and Immunology

GEBS Cluster Affiliations:
 IMV - Immunology, Microbiology, and Virology

University of Rochester
School of Medicine and Dentistry
601 Elmwood Ave, Box 609
Rochester, New York 14642

Phone: (585) 273-1402
Fax: (585) 273-2452
E-Mail: weiping_zheng@urmc.rochester.edu

Molecular Mechanisms for T cell Activation and Functional Differentiation

CD4 T cells play a key role in determining the immune responses that occur in response to exogenous and self antigens, through the production of different sets of cytokines. The cytokines mediate many of the functions of CD4 T cells and the unique cytokine profiles of the CD4 T cells define their functional subsets. The most distinct subsets of CD4 T cells are the type I and type II T helper cells (Th1 and Th2 cells). It appears that Th1 cells promote destructive inflammatory responses whereas Th2 cells promote humoral immune responses. Both Th1 and Th2 cells are derived from naïve CD4 T cells after antigenic stimulation.

My lab is interested in the molecular events that lead to the differentiation of Th1 and Th2 cells from naïve CD4 T cells. We have isolated genes differentially expressed in either Th1 or Th2 cells by using representational difference analysis (RDA). One of the Th2-specific genes is the transcription factor GATA-3. We have shown that high levels of GATA-3 are essential for the expression of Th2 cytokines, and Th1 lineage cells from mice transgenic for GATA-3 ectopically produce Th2 cytokines. On the other hand, a homeobox transcription factor Hlx is specifically expressed in Th1 cells. In mice transgenic for Hlx, there an increase in the number of Th1 cells, and the levels of IFN-gamma were elevated (total levels, and levels per individual T cell). Thus, Hlx and GATA-3 play causative roles in the differentiation of Th1 and Th2 cells, respectively.

Future work will focus on DNA-protein and protein-protein interactions related to these two transcription factors that are important in the establishment and maintenance of the Th1 and/or Th2 phenotypes. We will also characterize the functions of the other subset-specific genes using molecular, cellular and biochemical approaches. The ultimate goal of these studies is to provide a clear picture of the molecular pathways that lead to the differentiation and functional activation of Th1 and Th2 cells.

Zheng WP, Zhao Q, Zhao X, Li B, Hubank M, Schatz DG, Flavell RA. Up-Regulation of Hlx in Immature Th Cells Induces IFN-gamma Expression. J Immunol. 172:114-122, 2004.

Lu B, Yu H, Chow C, Li B, Zheng W, Davis RJ, Flavell RA. GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells. Immunity. 14:583-90, 2001.

Li B, Yu H, Zheng W, Voll R, Na S, Roberts AW, Williams DA, Davis RJ, Ghosh S, Flavell RA. Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation. Science 288:2219-22, 2000.

Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89:587-96, 1997.

Zheng WP, Kiura K, Milisauskas V, Nakamura I. Murine NK cell allospecificity-1 is defined by inhibitory ligands. J Immunol 156:4651-4655, 1996.

Zheng WP, Kiura K, Nakamura I. Dd is the only gene that controls NK cell resistance of heterozygous H-2b/d cells. Mol Immunol 32:773-776, 1995.

Zheng WP, Nakamura I. Immunological screening of homologous recombination in genes that encode surface antigens. BioTechniques 18:740-742, 1995.

Zheng WP, Milisauskas V, Nakamura I. Possible positive recognition of class I MHC molecule H-2Dd by natural killer cells. Natural Immunity 14:67, 1995.