Biographical Sketch

Dr. Zhou received his M.D. degree from Nanjing Medical University in China in 1996, and earned his Ph.D. degree in Microbiology, Immunology, and Molecular Genetics at the University of California – Los Angeles in 2004 in the laboratory of Dr. Stephen T. Smale.  He subsequently undertook an Irvington Institute for Immunological Research Post-doctoral Fellowship at the Skirball Institute at New York University in the laboratory of Dr. Dan R. Littman.  Dr. Zhou joined Northwestern University as an assistant professor in 2009 and currently holds a dual appointment in the Department of Pathology and the Department of Microbiology and Immunology.

Contact Information:

Liang Zhou, Ph.D.
Assistant Professor of Pathology and Microbiology-Immunology
Northwestern University Feinberg School of Medicine
303 E. Chicago Ave., Ward 3-120
Chicago, IL 60611

l-zhou@northwestern.edu
(312) 503-3182 Office

(312) 503-8240 Fax

Research Abstract

The long-term research goal of our laboratory is to determine how environmental factors interface with and affect the human immune system.  The links among autoimmune diseases, infections, cancer, and the environment are complex and mysterious.  Second-hand smoke, chemicals in the food or the air, UV exposure, and other forms of environmental pollution are among the triggers known to provoke the onset of autoimmune diseases and cancer.  Proper immune responses are needed to fight harmful microorganisms and tumor cells, yet those same responses have to be kept from overreacting and attacking the body’s normal tissues. 

The T helper cell (Th) paradigm has been used to explain how different adaptive immune responses are elicited in the host organism to clear infections with diverse microbial pathogens.  Th17 cells, a newly defined subset of T helper cells, secrete signature cytokines interleukin (IL)-17, IL-17F, and IL-22.  Th17 cells expressing transcription factor RORgt have been shown to play an important role in maintenance of mucosal integrity and immunity.  On the other hand, dysregulated Th17 responses result in autoimmunity both in mice and in humans.  Another subset of CD4⁺ T cells, the regulatory T cells (Tregs), suppresses effector T cell responses and prevents their potentially pathogenic effects.  It has been shown that the Forkhead transcription factor Foxp3 is required for Treg cell development and function.  T helper cell differentiation requires specific cytokine milieu.  Recently, we and others showed that IL-6 induces IL-21 and the IL-23 receptor (IL-23R) in a sequential manner.  IL-21 and IL-23 signaling, in concert with TGF-β, program naïve T cells into the Th17 lineage independently of IL-6.  We have discovered that TGF-β orchestrates Th17 and Treg cell differentiation program in a concentration-dependent manner, through modulation of RORgt and Foxp3 balance and interaction.  Currently, we are characterizing the interactions between various transcription factors involved in specifying development of Th17 cells and the related iTreg lineage and how they eventually determine whether the T cell adopts the Th17 or Treg cell fate.  We are also characterizing signaling pathways that govern the differentiation choice of Th17 vs. Treg cells.

The innate lymphoid cells (ILCs) represent an emerging family of cells that lack T cell receptor but secrete cytokines produced by T helper cells.  Among them, RORgt⁺ ILCs consist of heterogeneous cell populations that secrete Th17-associated cytokines (e.g., IL-17 and IL-22).  RORgt⁺ ILCs have been implicated in intestinal immunity and inflammation.  Our laboratory is interested in understanding transcriptional regulation of RORgt⁺ ILCs.  Recently, we have shown the molecular regulation of RORgt⁺ ILCs by the aryl hydrocarbon receptor (Ahr), a ligand-dependent transcription factor.  Ahr acts as an environmental sensor by binding to a variety of xenobiotic chemicals and endogenous metabolites.  We have shown that Ahr is required for the maintenance and function of RORgt⁺ ILCs in the gut.  This work has implications for understanding how to modulate intestinal immune responses in different disease settings (e.g., human IBD and/or infectious disease).  Using novel genetic approaches, we are currently determining whether Ahr interacts with other factors to regulate a set of target genes in order to perform critical biological functions in RORgt⁺ ILCs, whereby influencing gut immunity. 

Our lab employs a combination of molecular, biochemical, and mouse genetic approaches to dissect the signaling pathways and unravel the functions of various transcription factors in T helper cell and innate lymphoid cell development.  We believe that understanding the differentiation of Th17 and Treg cells at molecular levels and dissecting the transcription regulation of RORgt⁺ ILCs will shed light on the crosstalk between the host immune system and the environment (e.g., environmental pollutants, gut flora, and dietary components).  Our research will provide novel insights into the pathogenesis of inflammatory diseases and may eventually lead to identification of new therapeutic targets for treating human autoimmune and inflammatory diseases and cancers.

Publications

Qiu, J., Heller J. J., Guo, X, Chen Z. E, Fish, K., Fu Y-X, and Zhou, L.  The Aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells.  Immunity.  36 (1), 92-104 (2012).

Heller, J. J., Qiu, J., Zhou, L. Nuclear receptors take center stage in T_H17-mediated autoimmunity.  J. Clin. Invest. 121 (2), 519-521 (2011).

DieCruz-Orengo L., Holman D. W., Dorsey D., Zhou, L., Wright, M., McCandless, E. E., Patel, J. R., Piccio, L., Luker, G. D., Cross A. H., Littman, D. R., Russell, J. H., Klein, R. S. CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity.  J. Exp. Med. 208 (2), 327-39 (2011).

Rodgers, J. M., Zhou, L., Miller, S. D. Act1, scene brain: astrocytes play a lead role.  Immunity. 32, 302-04 (2010).

Martin, A. J. Zhou, L., Miller S. D. MicroRNA-managing the TH17 inflammatory response. Nat. Immunol. 10 (12), 1229-31 (2009).

Zhou, L., Chong, M. M. W., Littman, D. R.  Plasticity of CD4⁺ T cell lineage differentiation.  Immunity. 30 (5), 646-55 (2009).

Zhou, L., Littman, D. R.  Transcriptional regulatory networks in T_H17 cell differentiation.  Curr. Opin. Immunol.  21 (2), 146-52 (2009). 

Zhou, L., Lopes, J., Chong, M. M. W., Ivanov, I. I., Min, R., Victora, G. D., Shen, Y., Du, J., Rubtsov, Y. P., Rudensky, A. Y., Ziegler, S. F., Littman, D. R. TGF-b-induced Foxp3 inhibits T_H17 cell differentiation by antagonizing RORgt function.  Nature.  453 (7192), 236-40 (2008). 

Ivanov I. I., Zhou, L., Littman, D. R.  Transcriptional regulation of T_H17 cell differentiation.  Semin. Immunol.  19 (6), 409-17 (2007).

Zhou, L., Ivanov, I. I., Spolski, R., Min, R., Shenderov, K., Egawa, T., Levy, D. E., Leonard, W. J., Littman, D. R.  IL-6 programs T_H17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.  Nat. Immunol.  8 (9), 967-74 (2007).

Zhou, L., Nazarian, A. A., Xu, J., Tantin, D, Corcoran, L. M., Smale, S. T.  An inducible enhancer required for Il12b promoter activity in an insulated chromatin environment.  Mol. Cell. Biol.  27 (7), 2698-712 (2007).

Ivanov, I. I.*, McKenzie, B. S.*, Zhou. L. *, Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J., Littman, D. R.  The orphan nuclear receptor RORgt directs the differentiation program of proinflammatory IL-17⁺ T helper cells.  Cell.  126 (6) 1121-33 (2006).  *equal contributions

Sanjabi, S., Williams, K., Saccani, S., Hoffmann, A., Zhou, L., Gerondakis, S., Baltimore, D., Natoli, G., Smale, S. T.  A c-Rel subdomain responsible for enhanced DNA-binding affinity and selective gene activation.  Genes Dev.  9 (18), 2138-51 (2005).

Zhou, L., Nazarian, A. A., Smale, S. T.  Interleukin-10 inhibits interleukin-12 p40 gene transcription by targeting a late event in the activation pathway.  Mol. Cell. Biol.  24 (6), 2385-96 (2004).

Bradley, M. N., Zhou, L., Smale, S. T.  C/EBPb regulation in lipopolysaccharide-stimulated macrophages.  Mol. Cell. Biol.  23 (14), 4841-58 (2003).

Yu, M. C., Orlando, T. C., Sturm, N. R., Zhou, L., Saito, R. M., Floeter-Winter, L. M., Campbell, D. A.  Two distinct functional spliced leader RNA gene arrays in Leishmania tarentolae are found in several lizard Leishmania species.  Int. J. Parasitol.  32 (11), 1411-22 (2002).

Feng, H., Zhong, W., Punkosdy, G., Gu, S., Zhou, L., Seabolt, E. K., Kipreos, E. T.  CUL-2 is required for the G1-to-S-phase transition and mitotic chromosome condensation in Caenorhabditis elegans.  Nat. Cell Biol.  1 (8), 486-92 (1999).