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Faculty Leo Lefrancois
Professor of Immunology
Chief, Division of Immunology
lefrancois@nso1.uchc.edu
 Areas
of Interest:
The
main focus of my research is to understand the control of the immune
response against microbial infections and against self-antigens. Since
many pathogens enter via mucosal tissues and since many autoimmune
diseases are organ-specific, it is critical to study the immune system
beyond the more traditional analysis of lymphocytes in the spleen and
lymph nodes. Thus, in the context of antimicrobial and autoimmune
responses my lab is interested in the interrelationships between the
secondary lymphoid immune system and the immune systems of tertiary
organs such as the intestine and the lung. Using mouse models and
adoptive transfer systems, 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.
Publications
Selected Publications:
Schluns, K.S., Klonowski, K.D. and Lefrancois, 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.
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