Yang-Xin Fu, M.D., Ph.D.
Molecular Mechanisms Underlying Lymphoid
Microenvironment Formation and Immune Response, and its Role in
Vaccination, Autoimmunity, and Tumor Immunity
My clinical background and strong interest in basic immunobiology have led me to integrate basic research into more pathogenesis and treatment of diseases. The basic research in my laboratory is focused on understanding the biological consequences arising from the interaction between core molecules of the TNF superfamily, lymphotoxin (LT or TNFSF1) and LIGHT (TNFSF14), on lymphocytes, and their receptor, LTbR, on stromal cells. This research has contributed substantially to the definition of the critical role these molecules play in the development and function of lymphoid tissues. Our recent studies have defined the roles of these molecules in infectious and tumor immunity in mouse models and human patients. Our research includes four major themes.
Critical role for lymphotoxin in the development and function of primary, secondary, and tertiary lymphoid tissues
The relative contributions of lymphoid tissues and non-lymphoid tissues to various immune responses had not been defined previously due to the lack of appropriate animal models and the complicated nature of the issues involved. Our pioneering studies have revealed the essential role of LT and TNF for the development and maintenance of lymphoid tissues. Using LT-deficient mice, or antibody or soluble receptor blockade, we generated unique mouse models that lack various sets of secondary lymphoid tissues to define the roles of these structures in various tissues for different types of immune responses. We have been studying the development and maintenance of complex lymphoid architecture using these models; Lately, we are exploring novel LTbR-stimulated NFkB pathways shape the development and function of lymphoid tissues which are important for priming and tolerance. Recently, we have been exploring the role of LT-controlled gut immunity in acute colitis.
The role of gut immunity in obesity and diabetes
While the existing paradigm simply attributes obesity to caloric imbalance, recent studies show that the commensal microbiota is required for high fat diet (HFD)-induced obesity. Major gaps in our understanding of diet induced obesity (DIO) are the lack of knowledge on the interplay between the microbiota, gut epithelial cells, and immune cells in response to HFD that promote obesity. Our novel discovery highlights that the lymphotoxin (LT) pathway, a key molecule in gut immunity, could control DIO as demonstrated by the observation that LTβR-/- and LTα-/- mice strongly resist DIO. The cecal bacterial community of LTβR-/- animals was dysregulated and cecal transplantation conferred leanness to germ free recipients. Housing LTβR-/- mice with their obese siblings rescued weight gain and demonstrated the communicable nature of the obese phenotype. LTβR-/- mice have a defect in antibacterial peptide production from intestinal epithelial cells. We hypothesize that HFD-induced changes to the microbiota, gut epithelial cells, and immune responses as a interaction loop is required for DIO. This study will open a new avenue for us to understand the molecular and cellular immune pathways that facilitate the formation of the obese microbiome and identify specific flora for experimental markers and targeted treatment of DIO.
Target tumor tissues to generate systemic immune responses
Lack of effective infiltration of immune cells and proper expression of co-stimulatory molecule prevent effective immune response against established tumor. Our understanding of the role of LIGHT on the LTbR-mediated lymphoid microenvironment and on its another receptor, HVEM (a costimulatory receptor) has allowed us to study the role of lymphoid-like microenvironment in autoimmune diseases and develop new strategies to target tumor with LIGHT to attract immune cells by LTbR signaling and activate T cells by HVEM inside tumor tissues. Indeed, local expression of LIGHT inside tumors causes development of lymphoid-like structures within those tumors. This allows the rapid recruitment of naïve and activated T cells into tumor sites and generates an effective anti-tumor response. Our future studies will attempt to reveal the cellular and molecular mechanisms governing tumor evasion and barriers in tumor bearing host. These basic studies will also guide us in the development of novel approaches to immunotherapy to break tumor barriers and tumor induced tolerance.
1. To investigate the mechanisms by which antibody based immunotherapy. We will explore the role of antibodies in induction of cytokines, stress molecules, and Fc receptor mediated cross-priming. Currently, we have targeted CD20, HER2/neu and EGFR.
2. To investigate the mechanisms by which short-term high dose RT initiates an immune response(s). We will explore which cells and cytokines are essential at initiating RT-mediated immunity.
3. To investigate whether targeting tumors with a novel fusion protein, consisting of anti-tumor antibody genetically fused to LIGHT, a potent immunostimulatory molecule, can further amplify the ablative RT+antibody (ablative RT+Ab) mediated immunity investigated above.
4. To determine the effects of currently used chemotherapeutic agents on radiation and anti-neu initiated anti-tumor immunity.
5. To determine the effect of endogenous danger signaling on triggering innate and adaptive immunity against tumor.
Kim KD, Zhao J, Auh S, Du P,. Yang, X., Tang H, and Fu YX. Adaptive immune cells temper initial innate responses. Nature Med 13:1248-1252, 2007 (see commentary entitled “Not so fast: adaptive suppression of innate immunity” in Nature Medicine (13: 1142-1144, 2007) and highlight entitled “T cells calm the storm” by Nature Review Immunogy.
Zhu M, and FuYX, Coordinating Development of Medullary Thymic Epithelial Cells, Immunity 29:388, 2008.
Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma R, Chin RK, Tu T, Weichselbaum RR, and Fu Y-X. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: Changing strategies for cancer treatment Blood. 114(3):589-95, 2009. PMID: 19349616
Wang Y, Koroleva EP, Kruglov AA, Kuprash DV, Nedospasov SA, Fu YX, Tumanov AV. (*co-corresponding author). LTbR signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity. 2010 Mar 26;32(3):403-13.
Thompson ED, Enriquez HL, Fu YX, Engelhard VH. Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. J Exp Med. 207(8):1791-804, 2010
Kim TS, Hufford MM, Sun J, Fu YX, Braciale TJ. Antigen persistence and the control of local T cell memory by migrant respiratory dendritic cells after acute virus infection. J Exp Med. 207(6):1161-72, 2010.
Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, Turner JR, Fu YX, Romero IL, Lengyel E, Peter ME. CD95 promotes tumour growth. Nature. 465(7297):492-6, 2010
Park SG, Jiang Z, Mortenson ED, Deng Liufu, Radkevich-Brown, O, Yang X, Sattar1, Yang Wang H, Brown NK, Greene M, Liu Y, Tang J, Wang S, and Fu YX. The Therapeutic Effect of Anti-HER2/neu Antibody Depends on Both Innate and Adaptive Immunity. Cancer Cell 18:160–170, 2010.
Zhu M, Fu YX. Deflating the lymph node. Immunity. 34(1):8-10, 2011.
Burnette B, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, Auh S, Fu YX. The Efficacy of Radiotherapy Relies Upon Induction of Type I Interferon-Dependent Innate and Adaptive Immunity. Cancer Research, 71:2488-2496, 2011.
Tumanov AV, Koroleva EP, Guo X, Wang Y, Kruglov A, Nedospasov S, Fu YX. Lymphotoxin Controls the IL-22 Protection Pathway in Gut Innate Lymphoid Cells during Mucosal Pathogen Challenge. Cell Host Microbe. 10(1):44-53, 2011.
Qiu J, Heller JJ, Guo X, Chen ZM, Fish K, Fu YX, Zhou L. The Aryl Hydrocarbon Receptor Regulates Gut Immunity through Modulation of Innate Lymphoid Cells. Immunity. 36(1):92-104, 2012.
Moseman EA, Iannacone M, Bosurgi L, Tonti E, Chevrier N, Tumanov A, Fu YX, Hacohen N, von Andrian UH. B Cell Maintenance of Subcapsular Sinus Macrophages Protects against a Fatal Viral Infection Independent of Adaptive Immunity. Immunity. 36(3):415-26, 2012.
Zou W, Zheng, H, He, T-C, Chang J, Fu, Y.-X, and Fan, W. LIGHT delivery to tumors by mesenchymal stem cells mobilizes an effective anti-tumor immune responses. Cancer Research. 72(12):2980-9, 2012.
Xiao X, Balasubramanian S, Liu W, Chu X, Wang H, Taparowsky EJ, Fu YX, Choi Y, Walsh MC, Li XC. OX40 signaling favors the induction of T(H)9 cells and airway inflammation. 2012 in press.
Vaibhav Upadhyay, Valeriy Poroyko, Tae-jin Kim, Suzanne Devkota, Sherry Fu, Donald Liu, Alexei V Tumanov, Ekaterina P Koroleva, Liufu Deng, Cathryn Nagler, Eugene Chang, Hong Tang, and Yang-Xin Fu Lymphotoxin regulates commensal responses to enable diet-induced obesity Nature Immunology, in press.
Faculty and Research