Yang-Xin Fu, MD, PhD

Cross-talk between immune and stromal cells establishes a microenvironment that is necessary for lymphoid tissue development, central and peripheral tolerance, and efficient migration of immune responses. However, little is known about the molecular mechanisms that underlie the interactions between lymphocytes and stromal cells. We propose that lymphotoxin (LT) from T cells and LTbR on stromal cells establishes a lymphoid microenvironment for cross-talk and efficient and self-contain immune responses. More specifically, a set of distinct adhesion molecules and tissue chemokines from stromal cells are regulated by lymphocytes for a flexible, delicate, and rapid immune response inside and outside lymphoid tissues. Our studies have revealed that lymphotoxin (LT), TNF, and LIGHT (another ligand for LT receptor) are key cytokines for establishing organized lymphoid structures inside and outside lymphoid organs/tissues critical for the development of lymphocytes and various immune responses.

Through upregulation or downregulation of LT/LIGHT core family members on different lymphocytes by gene targeting and antibody stimulation/blockade, our studies have revealed the contribution of LT/LIGHT pathway in the formation of primary and secondary lymphoid tissues and the development of various immune responses at the cellular and molecular level. Our studies also have revealed that LT receptor-mediated structures are critical in the pathogenesis of of chronic inflammation and various diseases. Locally expression of LIGHT inside tumor will convert tumor tissues becoming lymphoid-like structures which allow the recruitment of naïve T cells into tumor site leading to tumor rejection. We have set up new models to study autoimmune hepatitis, liver regeneration, asthma, chronic inflammation, autoimmunity, and tumor immunity. Using LT/LIGHT system as model, we have been able to tackle some key steps in autoimmunity and tumor immunity. The broad understanding of these disease processes has led to the better understanding of immunopathology and development of novel immunotherapies for several chronic diseases. Our disease-oriental studies have also allowed us to revisit several fundamental issues in immunobiology.

With this background, we will focus on following three areas:

1) We will study the role of lymphotoxin and related family members in the development and function of the lymphoid tissues for immune tolerance. Autoimmune regular (AIRE) is a newly discovered transcription factor regulating peripherally restricted antigens in thymic medulla epithelial cells (mTECs). Lack of AIRE in patients or mice led to increased incidences of endocrine organ-specific autoimmune diseases. Our preliminary data showed that lymphotoxin (LT) receptor signaling was necessary for the expression of self antigens in AIRE-dependent and independent pathway. Such model allows us to explore how atuoreactive T cells to peripheral antigens are deleted in thymus and the impact of impaired negative selection to autoimmunity. We will address whether and how LT controls the expression of autoantigens in both an AIRE-dependent and -independent pathways leading to negative selection of autoreactive T cells. LT-deficiency would lead to impaired negative selection compounded with persistent local inflammation leading to tissue-specific autoimmune destruction. The significance of negative selection is under investigation.
2) The role of lymphoid-like structures and lymph nodes in the pathogenesis of chronic inflammatory diseases. LT-deficient mice have multiple defects. We will dissect the role of LT vs lymphoid tissues in various defects, autoimmune diseases, infectious diseases, and inflammatory bowel diseases since lack of either LT or lymphoid tissues might contribute to the pathogenesis.
3) We are exploring and developing the novel treatments to break tumor barriers and tolerance. Our past studies have made significant contributions to determining the role of lymphoid tissues and lymphoid-like tissues in various immune responses, chronic inflammation, and autoimmunity. Over the last five years, we have established several animal models that have allowed us to explore the role of closely related LT/TNF superfamily members in immunity and tumor immunity. 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.