Complement fragments C3a and C5a: the salt and pepper of the immune response

The influence of complement on B-cell responses has been known for many years, but the notion that T-cell recognition, expansion and differentiation are complement dependent has only recently gained impetus. DC, and to a lesser extent T cells, produce a range of complement components necessary for complement activation, and these cells also express receptors that detect complement-activation products such as C3a and C5a (anaphylatoxins). In the absence of C3a-receptor (C3aR) signalling, DC lose their capacity to induce potent Th1 responses against alloantigen and also favour the emergence of Treg. A study in this issue of the European Journal of Immunology not only spotlights the importance of C5aR signalling in DC interaction with T cells, but also shows how cooperation with other signalling pathways determines the outcome of T-cell activation. Remove C5aR from the equation, TLR2-stimulated DC induce naive CD4(+) Th cells to undergo differentiation not only mainly to Th17 cells but also to Treg, via a TGF-beta-dependent pathway. Thus, anaphylatoxins in conjunction with other danger signalling pathways modify the function of DC in antigen presentation and help to shape the primary immune response. Future work will need to address the impact of anaphylatoxins on protective immunity in vivo and determine the wider implications of anaphylatoxins for allo- and autoimmunity.