Cellular characterization of the receptors for the C5a anaphylatoxin and their contributions to the innate and adaptive immune responses.

摘要

Complement is a critical component of the innate immune system tasked with host defense against invading pathogens. Complement also serves a crucial bridge between the innate and adaptive immune systems by augmenting adaptive immune responses, including T cell-mediated immunity. The activation of the complement system leads to the generation of the anaphylatoxins, potent pro-inflammatory molecules. Of the anaphylatoxins, C5a is the most potent and plays numerous roles in innate host defense. C5a mediates its inflammatory functions by interacting with the G protein coupled, 7-transmembrane receptors C5aR (CD88) and C5L2. C5aR is a well characterized receptor that evoked myriad signaling pathways leading to the inflammatory response. C5L2 is an enigmatic receptor that seems to be uncoupled from G proteins and has, until recently, been considered a decoy receptor to limit the actions of C5a. However, recent evidence has suggested that C5L2 transduces functional signals in some settings.;The work herein is to clarify the functions of the receptors for C5a. C5aR has been implicated as a major component of the ability of complement to modulate T cell responses. However, the mechanism by which it does so remains obscure. Part of the difficulty lies in discrepancies within the literature regarding the cellular distribution of C5aR on T cells and related antigen presenting cells. We have developed a novel GFP knock-in mouse model under the control of the C5aR promoter to attempt to clarify this discrepancy. Our results suggest that C5aR signaling is not intrinsic to T cells, but rather functions through a proxy of other innate cell types to evoke functional responses on T cell immune responses. We also attempted to clarify the manner in which C5L2 may transduce a functional signal by examining the G protein coupling potential of C5L2 in a comprehensive fashion.