Dendritic cells (DCs) are innate immune cells that regulate both immune homeostasis as well as antigendriven immune responses. The functions of DCs are highly regulated by signals initiated by Toll-likereceptors (TLRs). Consequently, intracellular molecules that regulate TLR signaling pathways are pivotal forregulating host immune responses. We have recently found that A20 is a ubiquitin modifying enzyme thatrestricts toll-like receptor (TLR) induced signals. We are studying the roles of A20 expression in DCs inregulating immune homeostasis and responses. To accomplish this, we have generated two strains of genetargeted mice: one that disrupts the A20 gene in all cells and one in which a 'floxed' allele of A20 has beentargeted to the endogenous A20 locus. We have interbred the 'floxed' mice with a novel strain of CD11-Cretransgenic mouse line that expresses Cre enzyme with high selectivity and specificity in DCs. Thesecompound A20flox/flox CD11c-Cre mice will thus provide us with a very powerful and novel reagent forstudying the role of A20 expression in DCs in regulating immune homeostasis and immune responses. Wepropose to use these A20flox/flox CD11-cre compound mice, as well as cells derived from both strains ofmice, to determine how A20 expression in DCs regulates their responses to TLR ligands in vitro and in vivo.
The first aim will focus upon understanding the cell biology and biochemistry underlying A20's roles inregulating TLR signaling in DCs, and will elucidate the cell-autonomous functions of DCs that are regulatedby A20.
The second aim will utilize A20flox/flox CD11c-Cre mice to determine how A20 expression in DCsregulates their homeostasis and activation in vivo.
This second aim will also interrogate how A20 expressionin DCs regulates peripheral tolerance and immune responses and prevents autoimmunity.These studies should teach us a great deal about how dendritic cells are normally regulated, and how theymay play a major role in preventing autoimmunity and regulating immune responses. They may also providenovel therapeutic targets for controlling inflammation.
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