Research

My laboratory is primarily interested in factors regulating T and B lymphocyte activation, function, longevity, and apoptosis, especially in animal models of systemic autoimmune disease. Particular attention has focused on the kinds of antigen that can activate potentially autoreactive B cells. Previous studies have shown that relatively low affinity autoreactive B cells can be very efficiently activated by autoantigens that have the capacity to engage both the B cell receptor and either Toll-like receptor 9 (TLR9) or TLR7. These antigens include natural chromatin, defined dsDNA fragments, and RNA-associated macromolecular complexes. Studies are underway to: (a) further characterize the nature of the autoantigens that fit this criteria; (b) compare gene expression profiles of B cells activated by either conventional foreign ligands or autoantigens; (c) evaluate the early signaling events that distinguish activation by autoantigens from activation by conventional foreign antigens; (d) compare the functional properties of B cells activated by BCR/TLR9 or BCR/TLR7 co-engagement; (e) identify specific inhibitors of the TLR9/7 activation pathways; and (f) explore mechanisms of cross-regulation between cytocolic and endosomal nucleic acids.

A second major interest involves the regulatory functions of Fas-ligand. Fas-ligand was originally identified as a pro-apoptotic transmembrane protein critically involved in the regulation of T cells by activation induced cell death. However, under certain conditions, Fas-ligand can also induce a strong pro-inflammatory response. Fas-ligand can be cleaved by a membrane metalloproteinase to yield a soluble product that had been reported to serve as a neutrophil chemokine. However, we have found that transmembrane Fas-ligand is the most potent pro-inflammatory form of the molecule and that it can trigger the rapid expression and release of a number of inflammatory chemokines. Studies are underway to: (a) evaluate the role of Fas/FasL interactions on T cell persistence in vivo; (b) explore the mechanisms by which Fas-deficient tumor specific T cells can mediate tumor regression; (c) develop the technology to specifically target naturally formed FasL microvesicles to tumor populations; (d) distinguish the Fas signaling cascades that trigger apoptosis as opposed to inflammatory cytokine release; and (e) determine the functional phenotype of mice genetically targeted to express only a membrane form of Fas-ligand.

A third topic of investigation involves animal models of pseudo-GVHD in which TCR transgenic T cells are specifically targeted to either MHC class II+ cells or to the vascular endothelium. The model is designed such that target antigen expression can be turned on or off to allow for the evaluation of antigen-dependent triggers of disease and antigen-independent amplification loops.  These studies have led to the identification of a unique profibrotic CD8 T cell subset that is involved in pulmonary fibrosis.

Rotation position open to work on topics related to the molecular mechanisms involved in theactivation and differentiation of both murine and human autoreactive Bcells.  The lab is particularlyinterested in innate sensors of cell damage, including members of the Toll-likereceptor and Pyhin receptor gene families.

Postdoctoral Research Associate Position available to work on topics related to the molecular mechanisms involved in theactivation and differentiation of both murine and human autoreactive Bcells.  The lab is particularlyinterested in innate sensors of cell damage, including members of the Toll-likereceptor and Pyhin receptor gene families.