T lymphocytes play a central role in the initiation and regulation of the adaptive immune response to antigen, whether foreign or native. The outcome of T cell engagement of antigen is determined by both positive and negative signals, costimulation and coinhibition, generated mainly by the interaction between the B7 family and their receptor CD28 family. We use a variety of experimental approaches to understand how new costimulatory and coinhibitory B7 family members regulate T cell activation and tolerance. Upon activation in lymphoid organs, T cells differentiate and migrate to the periphery where they carry out their effector functions. However, little is known about how costimulation and coinhibition control T cell responses in peripheral non-lymphoid organs where most diseases occur. Our long-term goal is to elucidate the mechanisms by which costimulation and coinhibition regulate T cells in peripheral non-lymphoid organs, and to translate the lessons learned in these studies towards developing new therapeutic strategies for immune-related diseases such as cancer, autoimmune disorders, infectious diseases, and transplantation rejection.
We have recently discovered a new member of the T cell costimulatory/coinhibitory B7 family, B7x (also called B7-H4 or B7S1), and have generated gene knock-out and transgenic mice. Current emphasis in the lab is placed in the following areas:
Functions of B7x and B7-H3 in T cell responses in vivo. B7x and B7-H3 are close homologues and form a subgroup within the B7 family. As B7x and B7-H3 are the newest members of the family, we know very little about the mechanisms that regulate their expression, their signaling pathways, and ultimately their biological roles. We are now using gene knock-out and transgenic mice to study the regulation of this subgroup's expression, the mechanisms used by them to inhibit T cell functions, and their corresponding receptors which are currently unknown.
Human cancer-associated B7x and B7-H3. We have recently shown that B7x and B7-H3 are highly expressed in human cancers and are associated with disease spread and poor outcome. We are testing our hypothesis that over-expressions of B7x and B7-H3 by human cancers represent previously unrecognized mechanisms of downregulating anti-cancer immune responses as well as new therapeutic targets. Additionally, we have found that about half of cancer patients have soluble B7x in the blood, which warrants further investigation of this biomarker for potential diagnostic and prognostic purposes.
Roles of B7x and B7-H3 in autoimmune diseases. Both B7x and B7-H3 are expressed in peripheral non-lymphoid organs, which positions them ideally to play critical roles in regulating T cell activation and tolerance in peripheral tissues. We are utilizing a variety of autoimmune disease mouse models to investigate possible functions of B7x and B7-H3 to limit, terminate, and/or attenuate self-reactive T cell responses in peripheral tissues. We hope to then apply this knowledge to develop new therapeutic strategies for autoimmune diseases.
Relationship between B7x and B7-H3 and infection. By co-evolving with the immune system, pathogens have developed remarkable strategies to circumvent host defenses. We are interested in the roles of B7x and B7-H3 during the communication between the immune system and pathogens. We believe that by studying the way pathogens influence immune responses we can learn how to control immunity.
New members of the immunoglobulin superfamily. The human genome contains more than eight hundred members of the immunoglobulin superfamily, with unknown functions for many of them. We are always interested in identification and characteration of new immunoglobulin superfamily members that can regulate T cell activation and tolerance.
Translational medicine of T cell costimulation and coinhibition. We are interested in translational research and seek to move our findings in basic research more quickly and efficiently into medical practice. FDA has approved two new drugs developed from the B7/CD28 family. We believe that research on T cell costimulation and coinhibition holds promise for development of novel therapies and diagnoses.