γδT-cell function in sepsis is modulated by C5a receptor signalling

P>We previously showed that gamma delta T cells are involved in the pathogenesis of sepsis, but, the underlying mechanisms remained unclear. The present study demonstrates, for the first time, that gamma delta T cells express the complement C5a receptor (C5aR, CD88) and that CD88 expression in gamma delta T cells was up-regulated in mice following sepsis both at protein and mRNA levels. Complement C5a itself contributed to the regulation of C5aR expression on gamma delta T cells, as (i) neutralization of C5a in vivo prevented the expression of C5aR on gamma delta T cells in septic mice and (ii) incubation of mouse spleen cells or purified gamma delta T cells with recombinant C5a in vitro increased CD88 expression by gamma delta T cells at both protein and mRNA levels. C5a receptor on gamma delta T cells also mediates increased interleukin-17 (IL-17) expression as incubation of mouse spleen cells or purified gamma delta T cells with recombinant C5a promotes the IL-17 expression by gamma delta T cells. Ligation of the C5aR on gamma delta T cells activated the phosphoinositide 3-kinase (PI3K)/Akt signalling pathway, which enhances CD88 expression and promotes IL-17 secretion. These results demonstrate that C5a acts directly on the C5aR expressed on gamma delta T cells, resulting in cell activation, and subsequently enhances their capacity for IL-17 production. The up-regulation of the PI3K/Akt pathway following C5a stimulation contributes to up-regulation of gamma delta T-cell function.