Locally produced C5a binds to T cell–expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis

PN Lalli, MG Strainic, M Yang, F Lin… - Blood, The Journal …, 2008 - ashpublications.org
PN Lalli, MG Strainic, M Yang, F Lin, ME Medof, PS Heeger
Blood, The Journal of the American Society of Hematology, 2008ashpublications.org
Our recent studies have shown that immune cell–produced complement provides
costimulatory and survival signals to naive CD4+ T cells. Whether these signals are similarly
required during effector cell expansion and what molecular pathways link locally produced
complement to T-cell survival were not clarified. To address this, we stimulated monoclonal
and polyclonal T cells in vitro and in vivo with antigen-presenting cells (APCs) deficient in
the complement regulatory protein, decay accelerating factor (DAF), and/or the complement …
Abstract
Our recent studies have shown that immune cell–produced complement provides costimulatory and survival signals to naive CD4+ T cells. Whether these signals are similarly required during effector cell expansion and what molecular pathways link locally produced complement to T-cell survival were not clarified. To address this, we stimulated monoclonal and polyclonal T cells in vitro and in vivo with antigen-presenting cells (APCs) deficient in the complement regulatory protein, decay accelerating factor (DAF), and/or the complement component C3. We found that T-cell expansion induced by DAF-deficient APCs was augmented with diminished T-cell apoptosis, whereas T-cell expansion induced by C3−/− APCs was reduced because of enhanced T-cell apoptosis. These effects were traced to locally produced C5a, which through binding to T cell–expressed C5aR, enhanced expression of Bcl-2 and prevented Fas up-regulation. The results show that C5aR signal transduction in T cells is important to allow optimal T-cell expansion, as well as to maintain naive cell viability, and does so by suppressing programmed cell death.
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