Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis.
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.
Department of Immunology, Cleveland Clinic, OH, USA.
Peter N
PN
Lalli
Michael G
MG
Strainic
Min
M
Yang
Feng
F
Lin
M Edward
ME
Medof
Peter S
PS
Heeger
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D058544:Class Ib Phosphatidylinositol 3-Kinase; D003167:Complement Activation; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism; D015936:Complement C5a / Q000096:biosynthesis / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D018958:CD55 Antigens; D003176:Complement C3; C491899:Fas protein, mouse; D007527:Isoenzymes; D019253:Proto-Oncogene Proteins c-bcl-2; D044087:Receptor, Anaphylatoxin C5a; C521184:decay-accelerating factor 1, mouse; D019014:fas Receptor; D015936:Complement C5a; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse