- Professor, Department of Medicine - Section of Rheumatology, Committee on Immunology, Committee on Molecular Medicine/MPMM, Committee on Molecular Metabolism and Nutrition, Cancer Research Center
Ph.D., The University of Chicago, 1993
M.D., Université Libre de Bruxelles, 1985
B.S., Université Libre de Bruxelles, 1981
The University of Chicago
924 East 57th Street
Chicago, Illinois 60637
Phone: (773) 834-4317
T Cell Tolerance and Inhibitors of T Cell Function
The Alegre laboratory is interested in the molecular mechanisms that determine the activation and inhibition of T lymphocytes during diseases such as autoimmunity, rejection of solid organ transplants and cancer.
A particular focus of the laboratory is the study of the transcription factor NF-kB in T cells. Several immunosuppressive drugs, as well as many more in development, inhibit NF-kB as part of their mechanism of action. However, NF-kB is a ubiquitous transcription factor the inhibition of which can cause many severe side effects in different organ systems. Our laboratory has shown that T cell-restricted inhibition of NF-kB, using transgenic mice that express an NF-kB super-repressor selectively in T cells (IkBaDN-Tg mice), results in permanent acceptance of fully allogeneic cardiac allografts and development of donor-specific tolerance via apoptosis of alloreactive T cells. In these mice, T cell-NF-kB activity is inhibited downstream of several receptors, including the TCR, Toll-like receptors (TLRs) and tumor necrosis factor receptor (TNFR) family members. To determine whether selective inhibition of TCR-NF-kB is sufficient for preventing allograft rejection, we have obtained CARMA1-KO mice that lack an adaptor molecule required for selectively linking the TCR and BCR to NF-kB. CARMA1-KO mice also permanently accept fully allogeneic cardiac allografts, positioning the CARMA1-NF-kB axis as a very promising therapeutic target for clinical transplantation. Importantly, mice deficient in CARMA1 are an invaluable tool to understand the consequences of inhibition of this pathway on the development and differentiation of T cell subsets. Our current results indicate that genetic ablation of CARMA1 abolishes the thymic development of natural regulatory T cells (nTregs) but facilitates the conversion of conventional T cells into induced Tregs at high doses of TCR stimuli, revealing that CARMA1 plays opposite functions in the generation of nTregs versus iTregs. We are currently investigating the role of CARMA1 in the differentiation of Th17 cells as iTregs and Th17 differentiation is often reciprocally regulated. We aim to define the precise role of CARMA1 and TCR-driven NF-kB in the development/differentiation of T cell subsets in vitro and in transplantation models in vivo.
Another main interest centers on signals elicited by microbial infections and their consequences on immune responses to transplant antigens. One major goal in transplantation and autoimmunity is to develop new immunosuppressive agents with the potential to induce antigen-specific tolerance and thus avoid increased risk of infection and cancer in treated patients. Considerable effort has been spent on the study of costimulation-targeting therapies, as these regimens successfully induce permanent acceptance of transplanted organs such as heart grafts and pancreatic islets in rodents. However, in collaboration with Anita Chong, we have recently shown that infections at the time of transplantation potently antagonize the ability of costimulation-blockade therapies to achieve or maintain donor-specific tolerance. Our current studiesaim to understand the consequences of TLR signaling in vivo and should yield a deeper understanding of different facets of the interplay between innate and adaptive immune responses that may negatively impact establishment of tolerance in settings of transplantation and autoimmunity.