Leo Lefrançois, Ph.D.
Professor

University of Connecticut Health Center
Department of Immunology
263 Farmington Avenue
Farmington, CT 06030-1319
Telephone: (860) 679-3242
Fax: (860) 679-1868
email: Llefranc@neuron.uchc.edu

systems of tertiary organs such as the intestine and the lung.Using mouse models and adoptive MHC class I tetramer technology, and ELISPOT analysis we are able to track antigen-specific T cells throughout the body. This has led to some surprising findings regarding the character and the control of immune responses in non-lymphoid organs. A hypothesis that has emerged from these studies is that CD8 memory T cells comprise distinct pools of memory subsets in lymphoid (e.g., spleen) and non-lymphoid tissues. These results extend to CD4 T cells responding to infection, where distinct Th1 and Th2 responses are generated in different tissues. Ultimately, our studies could provide a basis for more rational vaccine design.

My laboratory has also developed transgenic mice expressing a model self antigen exclusively in the intestinal epithelium. These animals are being used in studies of the mechanism of deletion/regulation of autoreactive CD8 and CD4 T cells. Using these mice, a model system of intestinal disease has also been developed. In this system, antigen-specific CD8 T cells induce tissue damage only in the presence of inflammatory signals (e.g., virus infection). In the absence of these signals, tolerance is the outcome, either via anergy or deletion. Future studies hope to determine the antigen-presenting cell requirements for induction of tolerance versus disease and the mechanism by which intestine-specific antigen gains access to the secondary lymphoid tissues. We are also in the process of generating novel transgenic mice using tissue-specific inducible promoters and gene-deletion systems.

Overall, my research is skewed toward the use of in vivo model systems with the goal of understanding the requirements for induction and regulation of anti-microbial as well as autoreactive immune responses.

Using a variety of cell and molecular biological techniques the major questions we are focusing on are:

How are functional differences between lymphoid and non-lymphoid memory cells regulated?
What are the molecules involved in homing and migration of primary and memory antigen-specific T cells?
What are the important cytokines for control of primary and memory T cells?
How is tolerance generated and maintained to tissue-specific antigens?
Lab Rotation Projects:
1) Analysis of requirements for memory T cell lineage development in response to viral and bacterial infections.
2) Imaging of memory T cell localization in situ using confocal microscopy.
3) Assessing the role of CD4 T cell help in generation and maintenance of CD8 T cell memory.

Schluns, K.S., Klonowski, K.D. and Lefrançois, L. 2004. Trans-regulation of memory CD8 T-cell proliferation by IL-15Ra+ bone marrow-derived cells. Blood, 103:988-994.

Masopust, D., Vezys, V., Usherwood, E.J., Cauley, L.S., Olson, S., Marzo, A.M., Ward, R.L., Woodland, D.L. and Lefrançois, L. 2004. Activated primary and memory CD8 T cells migrate to nonlymphoid tissues regardless of site of activation or tissue of origin. J. Immunol., 172:4875-4882.

Schluns, K.S., Cabrera-Hernandez, A., Nowak, E.C., Puddington, L., Lefrançois, and Aguila, H.L. 2004. Distinct cell types control lymphoid subset development via IL-15 and Il-15Ra expression. Proc. Natl. Acad. Sci., 101:5616-5621.

Klonowski, K. D., Williams, K.J., Marzo, A.M., Lingenheld, E.G. and Lefrançois, L. Dynamics of blood-borne CD8 memory T cell migration in vivo. Immunity, in press.

Schluns, K.S., Williams, K., Ma, A., Zheng, X.X. and Lefrançois, L. 2002. Requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J. Immunol. Cutting Edge, 168:4827-4831.

D'Souza, W.N., Schluns, K.S., Masopust, D., Lefrançois, L. 2002. Essential role for IL-2 in the regulation of antiviral extralymphoid CD8 T cell responses. J. Immunol. 168: 5566-5572.

Vezys, V. and Lefrançois, L. 2002. Inflammatory signals drive organ-specific autoimmunity to normally cross-tolerizing endogenous antigen. J. Immunol. Cutting Edge, 169:6677-6680.

Masopust, D., Vezys, V., Marzo, A. and Lefrançois, L. 2001. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291:2413-2417.

Vezys, V., Olson, S. and Lefrançois, L. 2000. Expression of intestine-specific antigen reveals novel pathways of CD8 T cell tolerance induction. Immunity, 12:505-514.

Schluns, K.S., Kieper, W.C., Jameson, S.C., and Lefrançois, L. 2000. IL-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nature Immunology, 1:426-432.