Chairman, Committee on Immunology
Department of Pathology
The University of Chicago
Donnelley Biological Sciences Learning Center (BSLC)
Jules F. Knapp Medical Research Center (JFK)
924 E. 57th St., Room R-116
Chicago, IL 60637
Pathogenesis of autoimmune diseases is extremely complex. We are interested in organ-specific diseases such as autoimmune diabetes and psoriasis, and we have mouse models for both. Our studies focus on determining how T cells are initially activated in disease pathogenesis, how they home to the target organs, and how they destroy these organs.
We have found that aberrant positive selection of T cells is involved in autoimmunity. The role of this process in autoimmunity is addressed using transgenic mouse models. T cell receptors (TCRs) with an unusual feature (the ability to interact with both major histocompatibility complex (MHC) class I and MHC class II molecules) are being studied. Such T cells are common in mice with a limited diversity of MHC molecules and a limited diversity of peptides bound to the MHC. One such TCR, MM14.4, when expressed as a transgene, causes skin lesions most closely resembling human psoriasis. T cells carrying the MM14.4 TCR are selected into both CD4+ and CD8+ T cell subsets. Other dual-restricted receptors have been cloned, and additional transgenic mice carrying such receptors have been generated and are being analyzed.
Using a mouse model for autoimmune diabetes, we have started a new project to investigate the involvement of innate Toll-like receptors (TLRs) in autoimmunity. TLRs are involved in responses to infection with pathogens, but also maybe involved in the activation of non-infectious immunity. These studies will help to solve the longstanding riddle of how infection with pathogens is connected to autoimmunity.
To address the issue of the homing of effector T cells to their targets, we used insulin-specific CD8+ T cells (IS-CD8+). Homing is a multi-step process that involves increased adhesion between T cells and endothelial cells and subsequent extravasation (diapedesis). Our studies of the molecular mechanisms of IS-CD8+ cell trafficking to the islets have revealed a specific chemokine, CCL21, participating in firm adhesion. Using a genetic approach, we obtained new gene expression data on molecules involved in T cell homing to the pancreas. Analysis of changes in gene expression in the pancreas from mice treated with interferon gamma revealed that several chemokines were upregulated in response to such treatment. The role of these chemokines in the extravasation of islet-specific T lymphocytes is being studied. In addition, we determined that homing of IS-CD8+ cells to the pancreas is controlled genetically, and that some mouse strains do not support homing of IS-CD8+ cells. We are currently studying the underlying mechanisms, an understanding of which would allow us to suggest new therapeutic measures to stop the trafficking of auto-aggressive T cells to their targets.
We are also interested in how T cells that have reached their targets destroy them. We have been focusing on the Fas-mediated pathway of induced cell death. We previously determined that pancreatic cells can express Fas under the influence of as yet unknown signals from infiltrating T cells. We have now identified the nature of the signal. We have also generated mice with a conditional knock-out of Fas in cells, and we are studying diabetogenesis in these mice under conditions when Fas is permanently removed from cells during pathogenesis.
Another project deals with development and function of specialized epithelial cells, termed M cells. M cells are necessary for transepithelial transport of microbes for the purpose of probing the microflora for the presence of pathogens, and are closely associated with B lymphocytes. While studying the role of factors in the Tumor Necrosis Family most commonly involved in organogenesis, we found that production of these factors by B cells was completely dispensable for M cell generation. Studies of other signaling pathways potentially involved in molecular conversation between B and M cells are in progress.