Laboratory of Immunology

Program Description

Lymphocytes, CD4 T cells in particular, play a central role in orchestrating adaptive immune responses. After being activated through their T-cell receptor (TCR) in a particular cytokine milieu, naive CD4 T cells differentiate into distinct Th lineages, including Th1, Th2, and Th17 cells, which are indispensable for different types of immunity to various microorganisms. Other CD4 T cells include follicular T cells (Tfh) and regulatory T cells (Treg). Tfh cells are critical for promoting antibody responses, whereas Treg cells, which consist of naturally occurring regulatory T cells (nTregs) and inducible regulatory T cells (iTregs), are involved in maintaining immune tolerance and lymphocyte homeostasis. Inappropriate Th responses to pathogens may lead to chronic infection and/or tissue damage to the host. Similarly, unnecessary activation of Th1, Th17 or Th2 cells by harmless environmental- or self-antigens can cause organ-specific autoimmune diseases or allergic inflammatory diseases.

Differentiation of Th cells is tightly regulated by the networks of specific transcription factors (Fig.1). At present, the master regulators of Th lineages that have been identified include T-bet/Stat4 (Th1), GATA-3/Stat5 (Th2), RORγt/Stat3 (Th17), Foxp3/Stat5 (Treg) and Bcl-6/Stat3 (Tfh), respectively. However, emerging data suggest that there are many more critical transcription factors in the regulatory network that are critical for T-cell fate determination and function. In addition, the expression of these factors may not be mutually exclusive, in some cases resulting in massive heterogeneity of CD4 T cells.

Our knowledge on lineage-specific gene expression and cis DNA regulatory elements that are critical for expression of these genes in CD4 Th subsets is very limited. A complete understanding of how transcription factor complexes are regulated and how they precisely control Th cell heterogeneity, plasticity, and stability has great implication in designing strategies to treat a broad range of immune-related diseases, including chronic bacterial and viral infections such as HIV, autoimmune diseases, allergic diseases, and cancers.

Fig. 1. The Network of transcription factors in CD4 T cells Immunol Rev. 238:247-62, 2010.

To identify and study Th lineages and their subsets at finer levels, multi-color “reporter” mice reflecting the expression of key transcription factors are being prepared using BAC transgenic or knock-in strategies. T-bet-GFP reporter mice have been successfully generated (Fig.2). By using these indicator mice, MCIU will compare the gene expression patterns and epigenetic modifications in “pure” Th cells generated in vivo to identify lineage-specific genes. Lineage-specific genes found in mice studies will be verified in human T cells, and some of these genes may serve as new biomarkers for identifying human T-cell subsets and/or targets for treating specific human diseases. Fate-mapping experiments to address T-cell plasticity and its molecular mechanisms will be performed using reporter mice in which inducible-Cre expression is under the control of cytokine or transcription factor locus.

Fig. 2 T-bet-ZsGreen reporter is a faithful marker for Th1 cells. Naïve CD4 T cells from T-bet-ZsGreen BAC transgenic mice were primed under Th1, Th2 or Th17 conditions for 3 days in vitro. FACS analysis was carried out to determine expression of T-bet reporter. T-bet-ZsGreen expression was detected only in Th1 but not in Th2 or Th17 cells.

To elucidate molecular mechanisms of lineage-specific gene regulation, chromatin immunoprecipitation followed by high throughput sequencing (ChIPseq) will be applied to assess genome-wide epigenetic modifications in different cell types, including cells from genetically modified mice, and to map DNA binding sites for key transcription factors. The biological significance of these elements will be assessed by gene expression analyses through RNAseq. Using cross-species conservation analysis in combination with analyses of ChIPseq results from different T-cell subsets, potentially important cis-regulatory elements will be prioritized and selected as candidate regions to search for mutations or SNPs that result in immune-related human diseases.

Th-cell differentiation requires signals from innate cells such as dendritic cells (DCs), macrophages, natural killer cells (NKs), basophils, and newly defined non-B non-T (NBNT) cells (NHC, Nuocyte, MPP^type2, Ih2). Interestingly, these innate cells also express many transcription factors that are found in T cells, suggesting that a given transcription factor may regulate one particular type of immune response in different immune cells. The MCIU is investigating transcriptional regulation in innate cells that are critical for the initiation and/or amplification of Th-cell differentiation.

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Biography

Dr. Zhu received his bachelor’s degree summa cum laude from the department of biology, NanKai University, Tianjin, China, and his Ph.D. in biochemistry and molecular biology from the Shanghai Institute of Biochemistry (now known as Shanghai Institute of Biochemistry and Cell Biology), Chinese Academy of Sciences. He joined the Laboratory of Immunology (LI), NIAID, first as a Visiting Fellow and then as a staff scientist studying CD4 T-cell differentiation. He became a principal investigator in LI in October 2011.

He is interested in investigating heterogeneity and plasticity of immune cells and their functions during normal and pathological immune responses at cellular and molecular levels. His focus is on induction and functions of transcription factor complexes during development, lineage commitment, and maintenance of immune cells, particularly CD4 T helper (Th) cells.

Special Interest Groups
Immunology Interest Group (IIG), Cytokine Interest Group (CIG)

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Research Group

Suveena Sharma, Ph.D., Biologist
Ryoji Yagi, Ph.D., Research Fellow
Fang Yu, Ph.D., IRTA Fellow

From left to right: Jinfang Zhu, Fang Yu, Suveena Sharma, Ryoji Yagi.

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Selected Publications

Wohlfert EA, Grainger JR, Bouladoux N, Konkel JE, Oldenhove G, Ribeiro CH, Hall JA, Yagi R, Naik S, Bhairavabhotla R, Paul WE, Bosselut R, Wei G, Zhao K, Oukka M, Zhu J, Belkaid Y. GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice. J Clin Invest. 2011 Nov 1;121(11):4503-15.

Wei G, Abraham B, Yagi R, Jothi R, Cui K, Sharma S, Narlikar L, Northrup DL, Tang Q, Paul WE, Zhu J, Zhao K. Genome-wide analyses of transcription factor GATA3-mediated gene regulation in distinct T cell types. Immunity. 2011 Aug 26;35(2):299-311.

Yagi R, Junttila IS, Wei G, Urban JF Jr, Zhao K, Paul WE, Zhu J. The transcription factor GATA3 actively represses the Runx3 protein-regulated production of interferon-gamma. Immunity. 2010 Apr 23;32(4):507-17.

Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol.2010 Mar;28:445-89.

Zhu J, Davidson TS, Wei G, Jankovic D, Cui K, Schones DE, Guo L, Zhao K, Shevach EM, Paul WE. Down-regulation of Gfi-1expression by TGF-beta is important for differentiation of Th17 and CD103+ inducible regulatory T cells. J Exp Med. 2009 Feb 16;206(2):329-41.

Zhu J, Min B, Hu-Li J, Watson CJ, Grinberg A, Wang Q, Killeen N, Urban JF Jr, Guo L, Paul WE. Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat Immunol. 2004 Nov;5(11):1157-65.

View a complete listing in PubMed.

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Position Available

Transcriptional regulation in immune cells

A postdoctoral fellow position is immediately available in the Molecular and Cellular Immunoregulation Unit (MCIU) in the Laboratory of Immunology, NIAID. The MCIU aims to address diversity and plasticity of CD4 T helper (Th) subsets, regulation of Th cell fates/functions and the expression of lineage-specific genes by transcription factor complexes, and cellular/molecular requirements for the development of distinct Th subsets. Projects include generation of multi-color “reporter” and fate-mapping murine models to study heterogeneous Th cell populations in autoimmune, allergic and infectious settings, as well as genome wide analyses of gene expression, epigenetic modifications and transcription factor binding in these subsets using RNAseq and ChIPseq technologies. We are also interested in studying transcriptional regulation in other immune cells and human CD4 T cells which may have implications in immune-related human diseases.

We are seeking highly motivated and collaborative individuals capable of independent reasoning and excited about learning new technologies. The candidates must have a Ph.D. or M.D. degree with less than five years of postdoctoral experience. Preference will be given to candidates who have knowledge in immunology, in vivo animal models, human diseases or bioinformatics in high throughput datasets analyses. Previous experience in molecular and cellular biology is essential for the applicants without bioinformatics background. The candidates should have excellent writing and communication skills.

To apply, please send a short statement of your research goals, curriculum vitae, bibliography, and names and contact information of three references to Dr. Jeff Zhu jfZhu@niaid.nih.gov (email preferred) or to the following address:

Jinfang (Jeff) Zhu, Ph. D.
Molecular and Cellular Immunoregulation Unit
Laboratory of Immunology
National Institute of Allergy and Infectious Diseases
National Institutes of Health, DHHS
Building 10, Room 11D02
10 Center Drive
Bethesda, MD 20892-1892

NIH is dedicated to building a diverse community in its training and employment programs.

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