SCAVENGER RECEPTOR FUNCTION IN CHAPERONE-ELICITED ADAPTIVE IMMUNE RESPONSES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Scavenger receptors are pattern recognition receptors that bind and traffic a variety of endogenous and microbial ligands. The broad objective of our current studies is to define the mechanisms by which scavenger receptors modulate, and can be targeted to modulate, immune responses from leukocytes. Specifically, we are investigating: 1) how Scavenger Receptor Class-A (SR-A) functions to internalize bacteria and chaperones into antigen-presenting cells, and 2) how SR-A -expressing leukocytes contribute to ovarian cancer. A large part of our effort is directed towards Aim 1, which evokes from our identification of SR-A as a novel endocytic receptor for the molecular chaperones gp96 and CRT. With the use of SR-A-/- mice we have focused on elucidating the mechanisms by which scavenger receptors mediate the immunological effects of chaperones. Our recent data indicate that, in contrast to gp96 and other chaperones, CRT requires the addition of an exogenous adjuvant to elicit in vivo cytotoxic CD8+ T cell responses. These data were published in Bak et al. (2008). Our studies have recently expanded to identify the role of SR-A during bacterial infection with the use of dendritic cells (DCs) from SR-A-/- mice. Functional analyses demonstrated that SR-A is a critical phagocytic receptor for DC internalization of the gram-negative bacteria E. coli (Amiel et al., 2007). Current efforts are now directed at elucidating the interplay between SR-A and another family of cellular receptors for microbial products, the Toll-like receptors (TLRs). The studies described in this Abstract, together with other preliminary data, are the basis for a planned NIH grant submission.