Pamela J. Fink

T cells recognize foreign peptide antigens in the context of cell surface molecules encoded by the major histocompatibility complex. The T cell receptor (TCR) that mediates this specific recognition is a heterodimer consisting of alpha and beta chains. Both of these chains are encoded by separate gene elements that undergo rearrangement somatically, during the course of T cell differentiation within the thymus.

Work in Dr. Fink's laboratory centers around a transgenic line of mice that carries a rearranged Vß5+TCR ß chain gene in its genome. The alpha chains expressed by the T cells in these transgenic mice are encoded by endogenous genes that must undergo somatic rearrangement. These mice have been used to study the induction of self tolerance among mature peripheral T cells. An age-dependent deletion of populations of transgenic T cells is one result of encounter with a tolerogen that induces both phenotypic and functional changes in reactive T cells prior to their deletion. T cells in these animals also begin rearranging endogenous TCR ß chain genes, overcoming the barrier of TCR ß chain allelic exclusion. This process is called TCR revision, and results in a population of functional, self tolerant T cells expressing a diverse TCR repertoire. Current work focuses on the function of post-revision T cells.

Additional research in the lab centers on a novel function for Fas ligand, well known for its ability to deliver death signals through its receptor Fas. Fas ligand can also deliver a costimulatory signal inward, thereby enhancing antigen-specific proliferation of the Fas ligand expressing cell. FasL costimulation enhances antigen-specific proliferation and cytokine production and influences T cell maturation. Downstream mediators of signal transduction through Fas ligand have been defined, and the domains of the FasL molecule responsible for delivering this signal have been identified, and are distinct from those that induce death through Fas. We have also developed a method for tagging recent thymic emigrants in unmanipulated mice, and have discovered that RTEs undergo continued maturation in the lymphoid periphery. This maturation requires contact with secondary lymphoid organs. Future work is directed at determining whether RTEs can form long term memory and whether they are more prone to tolerance than are mature naive T cells.