Wei-ping Zeng, Ph.D.

Wei-Ping Zeng, Ph.D.Associate Professor
Department: Biochemistry and Microbiology
Research Cluster: Infectious and Immunological Diseases
Office: BBSC 336-K | Laboratory: BBSC 310
Phone: (304) 696-3892 | Fax: (304) 696-7207
E-mail: zengw@marshall.edu

 

Research Interests

CD4 T cells are the most important players of the immune system. The majority of them (~95%) are conventional CD4 T (Tcon) cells. They are responsible for immune responses against various infectious agents, therefore are essential for the survival of animals and humans in a nonsterile environment. However, when immune responses by CD4 Tcon cells are directed against self-antigens and allergens, they cause autoimmune and allergic diseases, such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis, inflammatory bowel diseases and asthma. To keep these “bad” CD4 Tcon cells in check, the immune system has evolved to contain a small “police army” (~5%) of regulatory CD4 T cells or Treg cells to stop the activation of the harmful CD4 Tcon cells.  Thus, the Treg cells are also essential for the health of the host such that animals and humans lacking Treg cells die of multi-organ autoimmune and allergic diseases at young age. The general goal of our research is to uncover the cellular, molecular and biochemical mechanisms that control the functions of CD4 Tcon and Treg cells.

Project 1. Mechanisms for Treg cell-mediated immune suppression

Treg cells are a recently discovered cell type of the immune system. Although their importance has drawn tremendous research interest from immunologists, it remains a mystery how Treg cells stop the activation of Tcon cells. We believe the key to solving this mystery lies in a transcription factor called Foxp3. Foxp3 is the “master regulator” of Treg cell development that is also essential for the function of the Treg cells. Therefore, it is highly likely that the products encoded by the target genes of Foxp3 are the molecules that mediate the suppression of CD4 Tcon cells. Based on this assumption, we have employed a variety of technologies, including microarray, ChIP-on-chip and genetic screening to identify Foxp3 target genes. By examining the effects of over-expression and down-regulation of these genes, we will determine which of them are important for suppressing Tcon cells. Once identified, such genes will be novel therapeutic targets for autoimmune and allergic diseases.

Project 2. Differentiation of CD4 Tcon into T helper (Th) cell subsets

Before activation by antigens, CD4 Tcon cells originated from the thymus are naïve, nonfunctional. When activated by antigens, they differentiate into 3 major Th cell subsets, i.e., Th1, Th2 and Th17 cells. These 3 Th cell subsets are the cellular basis of the diverse immune responses mediated by CD4 Tcon cells. Th1 cells are responsible for the clearance of intracellular infection, but may cause autoimmune diseases if reactive to self-antigens. On the other hand, Th2 cells provide immunity against worm infection, but may cause allergic diseases if reactive to allergens. Th17 cells reactive to self-antigens also cause autoimmune diseases. In the past, we identified GATA-3 as the master regulator of Th2 cell differentiation and Hlx as a key regulator of Th1 differentiation. Our current efforts are directed to understanding how the transcription factors important for Th subset differentiation recruit other regulatory proteins to form functional complexes, and how they interact with DNA sequences and/or chromatins to regulate gene expression.

Project 3. Cell lineage plasticity and inter-convertibility of Treg and Th cells

We have recently found that pathogenic Th cells that cause autoimmune and allergic diseases can gain Treg-like immune suppressive function when they were forced to express Foxp3. Conversely, Treg cells originated from the thymus can differentiate into Th1 cells, but they do not differentiate into Th2 and Th17 cells. These findings demonstrated certain degree of plasticity between the CD4 Tcon and Treg cell lineages. We are now investigating the molecular and biochemical mechanisms that prevent Treg cells from differentiating into Th2 and Th17 cells. On the clinical side, we are using the mouse models for inflammatory bowel diseases, multiple sclerosis and asthma to investigate the possibility to convert pathogenic Th cells to Treg-like cells for antigen-specific immune therapy of these diseases.

Research Descriptions

Functional subsets of CD4T cells.

Functional subsets of CD4 T cells. Naïve conventional CD4 T cells proliferate and differentiate into Th1, Th2 and Th17 effector cells after antigen stimulation in the presence of IL-12 and IFN-γ, il-4, il-6 and tgf-b, respectively. Th1 cells produce large amount of IFN-γ, th2 cells produce il-4, il-5 and il-13, th17 cells produce il-17 to mediate their respective immune functions. Regulatory t cells can block antigen activation of the naïve and th cells, therefore attenuating the immune response.

 

Regulation of Th differentiation.

Regulation of Th differentiation. Left, we used a cDNA subtraction technique called representational difference analysis to identify the transcription factor GATA-3 as the master regulator of Th2 differentiation. Southern blot analysis shows the enrichment of GATA-3 signals in Th2 cDNA samples after each round of subtraction by Th1 cDNA. Center, leishmaniasis is an infectious disease caused by abnormally high Th2 response to the infection. We found that expressing siRNA of a GATA-3 associated protein Pias1 in CD4 T cells can alleviate the disease. Right, in Th1 differentiation, we identified Hlx as a key regulator of Th1 differentiation. Conventional CD4 T cells from Hlx transgenic mice abnormally expressed IFN-γ even after differentiated under Th2-skewing conditions.

 

Cell lineage plasticity of Treg cells.

Cell lineage plasticity of Treg cells. Left, after differentiation under Th1-skewing conditions, Treg cells (Foxp3+) from healthy animals became “Th1” cells and produced IFN-γ. Center, however, the Treg cells could not become Th17 cells therefore failed to produce IL-17. Right, gene chip (microarray) analysis of gene expression identified transcriptional regulators preferentially expressed either in Treg (red) or CD4 Tcon (green) cells after differentiation under Th17-skewing conditions.

 

Therapeutic application of Foxp3-transduced Th cells in mouse models of human diseases.

Therapeutic application of Foxp3-transduced Th cells in mouse models of human diseases. Left, inflammatory bowel diseases (massive inflammatory infiltration in the colon) were induced by adoptive transfer of CD25-CD45RBh conventional CD4 T cells to immune deficient mice. However, co-transfer of Foxp3-transduced Th1 or Th17 cells greatly alleviate the diseases. Center and right, similarly, Foxp3-transduced Th cells suppressed disease development in the mouse models of multiple sclerosis and allergic asthma, respectively.

Selected Publications

Zeng WP (corresponding and senior author), Sollars VE, Belalcazar AD. 2011. Domain requirements for the diverse immune regulatory functions of foxp3. Mol Immunol 48:1932–1939

Zeng WP (corresponding and senior author), Chang C, Lai JJ. 2009. Immune suppressive activity and lack of T helper differentiation are differentially regulated in natural regulatory T cells. J. Immunol 183:3583

Zeng WP (corresponding and senior author), Chang C, Lai JJ. 2009. Immune suppressive activity and lack of T helper differentiation are differentially regulated in natural regulatory T cells. J. Immunol 183:3583

Hamalainen-Laanaya HK, Kobie JJ, Chang C and Zeng WP. 2007. Temporal and spatial changes of histone 3 K4 dimethylation at the IFN-γ gene during Th1 and Th2 cell differentiation. J Immunol 79:6410

Zhao X, Zheng B, Huang Y, Yang D, Katzman S, Chang C, Fowell D, Zeng WP. 2007. Interaction between GATA-3 and the transcriptional coregulator Pias1 is important for the regulation of Th2 immune responses. J Immunol 179:8297

Mikhalkevich N, Becknell B, Caligiuri MA, Bates M, Harvey R, Zheng WP. 2006. Responsiveness of naïve CD4 T cells to polarizing cytokines determines the ratio of Th1 and Th2 differentiation. J Immunol 176:1553

Young N, Mikhalkevich N, Yan Y, Chen D, Zheng WP. 2005. Differential regulation of osteoblast activity by Th subset mediated by parathyroid hormone and IFN-γ. J Immunol 175:8287

Zheng WP (corresponding and senior author), Zhao Q, Zhao X, Li B, Hubank M, Schatz DG, Flavell RA. 2004. Up-regulation of Hlx in immature T helper cells induces IFN- expression. J Immunol, 172:114

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

Laboratory Personnel

Adam Rashid (Graduate Student)