The anaphylatoxin C3a downregulates the Th2 response to epicutaneously introduced antigen.
Mechanical injury to the skin results in activation of the complement component C3 and release of the anaphylatoxin C3a. C3a binds to a seven-transmembrane G protein-coupled receptor, C3aR. We used C3aR(-/-) mice to examine the role of C3a in a mouse model of allergic inflammation induced by epicutaneous sensitization with OVA. C3aR(-/-) mice exhibited an exaggerated Th2 response to epicutaneous but not to intraperitoneal sensitization with OVA, as evidenced by significantly elevated levels of serum OVA-specific IgG1 and significantly increased secretion of the Th2 cytokines IL-4, IL-5, and IL-10 by antigen-stimulated splenocytes. Presentation of OVA peptide by C3aR(-/-) APCs caused significantly more IL-4 and IL-5 secretion by T cells from OVA-T cell receptor (OVA-TCR) transgenic mice compared with presentation by WT APCs. C3a inhibited the ability of splenocytes, but not of highly purified T cells, to secrete Th2 cytokines in response to TCR ligation. This inhibition was mediated by IL-12 secreted by APCs in response to C3a. These results suggest that C3a-C3aR interactions inhibit the ability of APCs to drive Th2 cell differentiation in response to epicutaneously introduced antigen and may have important implications for allergic skin diseases.
Division of Immunology, Children's Hospital and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Seiji
S
Kawamoto
Ali
A
Yalcindag
Dhafer
D
Laouini
Scott
S
Brodeur
Paul
P
Bryce
Bao
B
Lu
Alison A
AA
Humbles
Hans
H
Oettgen
Craig
C
Gerard
Raif S
RS
Geha
D000706:Anaphylatoxins / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D015926:Complement C3a / Q000235:genetics / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics* / Q000276:immunology*; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000032:analysis; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011951:Receptors, Complement / Q000172:deficiency*; D013154:Spleen / Q000166:cytology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
D000706:Anaphylatoxins; D007074:Immunoglobulin G; D015848:Interleukin-5; D011951:Receptors, Complement; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D015926:Complement C3a; D010047:Ovalbumin