Fas ligand (FasL, CD95L), a member of the TNF family of proteins, is best known for its ability to deliver apoptotic death signals through Fas (CD95). Work from our laboratory has demonstrated that FasL can also deliver costimulatory signals in the reverse direction. FasL-mediated costimulation enhances the in vivo and in vitro burst size of both polyclonal and monoclonal antigen-activated CD8+ T cells. Furthermore, FasL influences thymocyte maturation of T cells expressing receptors of moderate affinity for their selecting ligands. The mechanism of FasL-mediated costimulation and the nature of the transduced signal remain unexplored. One overall goal of the proposed experiments is to delineate how crosslinking FasL delivers a costimulatory signal, and how this signal is interpreted at the level of T cell function and the ability to mount an effective immune response to an invading pathogen. Fas interacts with FasL and transduces a death signal. Natural mutations in Fas that prevent initiation of this death cascade lead to lymphoproliferative disorders in both mice and humans. While it has been assumed that defective activation-induced cell death is one basis for this lymphoproliferation, it is not yet known whether expression of death-incompetent Fas molecules by T cells is necessary and sufficient to initiate lymphadenopathy and the accumulation of unusual Thy-1+B220+CD4-CD8- T cells. It is also unclear what Fas+ cell interacts with FasL+ T cells to deliver a costimulatory signal. A second overall goal of the proposed experiments is to investigate the role of Fas on activated T cells in lymphocyte homeostasis and to identify the Fas-expressing cell that initiates FasL-mediated costimulation. The following Specific Aims have been devised to address these goals.
Specific Aim 1 : To explore the mechanism of costimulation by reverse signaling through FasL.
Specific Aim 2 : To determine the in vivo consequences on immune responses of deficient costimulation through FasL.
Specific Aim 3 : To use mice bearing a floxed allele of Fas to determine in what cell population(s) loss of Fas expression drives the Ipr phenotype and to identify what cell costimulates T cell responses through FasL in vivo.
