Regulation of T cell immune responses by decay accelerating factor

The strength and type of a T cell immune response are key factors in determining the outcome in response to a given stimulus. Such factors affect clearance of bacterial, viral and parasitic infections, rejection of transplanted organs and the severity of autoimmune disorders. Recently, proteins of the complement system, traditionally considered components of the innate arm of the immune response, have been implicated as mediators of antigen-specific responses in both B cells and T cells. However, the precise mechanisms behind complement's influence on shaping T cell responses have not been fully elucidated. These studies demonstrate novel roles for complement activation in T cell responses, in particular, the role of the complement regulator decay accelerating factor as a control mechanism for T cell immune responses.; Decay accelerating factor (DAF) is a membrane bound complement regulator that controls progression of the complement cascade by promoting the decay of the alternative and classical pathway C3 convertases. Our initial studies of mice deficient in the murine homologue of DAF (Daf1) demonstrated increases in the production of interferon-gamma (IFNgamma) by responding T cells both in vitro and in vivo using an immunization model of T cell activation which was dependent on complement activation. Additionally, studies using skin graft models demonstrated an increase in graft rejection kinetics that was associated with an increase in anti-donor T cell responses.; Despite identifying DAF as a regulator of T cell responses, the precise mechanism behind increased IFNgamma responses in the absence of DAF was not completely clear. The strength of T cell responses are mediated by several factors including the expansion of responding cells by proliferation, contraction of these cells during the response, and the efficiency to which the cells initiate effector mechanisms. By investigating these factors in the absence of DAF, we initially demonstrated an increase in both proliferative rates of T cells as well as expansion of total cell numbers both in vitro and in vivo. Further investigation showed that in the absence of DAF, local constraints on complement activation were lifted, promoting the production of C5a. From this, we demonstrated that C5a binds to the C5aR expressed on T cells and influences survival of the responding T cells by regulating Fas/FasL-mediated apoptosis. In the absence of DAF, T cell survival was enhanced by preventing Fas and FasL upregulation in a C5a-dependent manner.; In addition to promoting cell survival, the absence of DAF on antigen presenting cells enhanced the ability of responding T cells to produce IFNgamma. Investigation into the mechanisms behind DAF's control of IFNgamma production by T cells identified a link between C5a and IL-12 production by antigen presenting cells. Enhanced production of C5a in the absence of DAF promoted IL-12 production by binding to the C5aR expressed on antigen presenting cells. The increase in IL-12 production and subsequent T cell IFNgamma production was diminished in the absence of APC-expressed C5aR and IL-12 as well as receptors for IL-12 expressed on the responding T cells. Overall, these studies have identified the complement regulator decay accelerating factor as a regulator of T cell responses by influencing T cell expansion, survival and differentiation into effector cells.