Sylvie Fournier
Associate Professor, Department of Microbiology and Immunology
Role of the B7/CD28/CTLA-4 costimulatory system in the maintenance of lymphocyte homeostasis and the development of autoimmunity.听
T lymphocytes require two signals for optimal proliferation and induction of effector functions. Signal one is delivered by the engagement of the T cell antigen receptor (TCR) with the peptide/MHC complex. Signal two is antigen-independent and provided by the ligation of accessory molecules called costimulatory receptors. The requirement for costimulatory signals to induce primary T cell responses suggest that the absence of costimulatory ligands may be a normal mechanism for the maintenance of peripheral T cell tolerance. The corollary of this is that aberrant expression of antigenic peptide/MHC complexes in conjunction with costimulatory ligands would lead to destructive autoimmune processes.听
The best-characterized costimulatory receptor expressed on resting T cells is CD28. CD28 is highly homologous to CTLA-4, an inducible protein expressed on T cells. In contrast to CD28, CTLA-4 is a negative regulator of T cell activation. Although these two receptors have opposing functions, they share common ligands. The B7 molecules, B7.1 (CD80) and B7.2 (CD86), are the counter-receptors for both CD28 and CTLA-4.听
To gain a better understanding of the influence and importance of the CD28/CTLA-4 system听in vivo, we have generated 3 independent transgenic mouse lines that constitutively express the ligand B7.2. This transgenic model has revealed previously unexpected function for the B7.2/CD28 system in the regulation of B cell and CD8+ T cell homeostasis and the development of autoimmune demyelinating disease in the nervous system. Using tools of both cellular and molecular biology, we study this transgenic model to understand the mechanisms that lead to disruption of lymphocyte homeostasis and the development of autoimunity.
- Estrada Guadarrama, JA., N'Diaye, MM., Wolak, K. and Fournier, S.听Neither perforin nor Fas deficiency prevents the development of a CD8+ T cell-mediated demyelinating disease (submitted, 2010).
- 听Exploring the roles of CD8(+) T lymphocytes in the pathogenesis of autoimmune demyelination. Semin. Immunopathol. 2010 Mar 18. [Epub ahead of print]
- 听Characterization of relapsing-remitting and chronic forms of experimental autoimmune encephalomyelitis in C57BL/6 mice. Glia. 58:434-45.
- 听Innate inflammatory responses to the Gram-positive bacterium Lactococcus lactis. Vaccine, 26:2689-99.
- (2006)听A pathogenic role for CD8+ T cells in a spontaneous model of demyelinating disease. 177(4):2403-11.
- (2006)听Transgenic Mice Expressing the p75 CCAAT-Displacement Protein/Cut Homeobox Isoform Develop a Myeloproliferative Disease鈥揕ike Myeloid Leukemia. 66(19):9492-501.
