title: An essential role for C5aR signaling in the optimal induction of a malaria-specific CD4+ T cell response by a whole-killed blood-stage vaccine.
abstract: The protective immunity induced by the whole-killed parasite vaccine against malarial blood-stage infection is dependent on the CD4(+) T cell response. However, the mechanism underlying this robust CD4(+) T cell response elicited by the whole-killed parasite vaccine is still largely unknown. In this study, we observe that immunization with Plasmodium yoelii-parasitized RBC lysate activates complement C5 and generates C5a. However, the protective efficacy against P. yoelii 17XL challenge is considerably reduced, and the malaria-specific CD4(+) T cell activation and memory T cell differentiation are largely suppressed in the C5aR-deficient (C5aR(-/-)) mice. An adoptive transfer assay demonstrates that the reduced protection of C5aR(-/-) mice is closely associated with the severely impaired CD4(+) T cell response. This is further confirmed by the fact that administration of C5aR antagonist significantly reduces the protective efficacy of the immunized B cell-deficient mice. Further study indicates that the defective CD4(+) T cell response in C5aR(-/-) mice is unlikely involved in the expansion of CD4(+)CD25(+)Foxp3(+) T cells, but strongly linked to a defect in dendritic cell (DC) maturation and the ability to allostimulate CD4(+) T cells. These results demonstrate that C5aR signaling is essential for the optimal induction of the malaria-specific CD4(+) T cell response by the whole-killed parasite vaccine through modulation of DCs function, which provides us with new clues to design an effective blood-stage subunit vaccine and helps us to understand the mechanism by which the T cell response is regulated by the complement system.
authors.affiliation: Department of Pathogenic Biology, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Taiping
authors.initials: T
authors.lastname: Liu
authors.forename: Guilian
authors.initials: G
authors.lastname: Xu
authors.forename: Bo
authors.initials: B
authors.lastname: Guo
authors.forename: Yong
authors.initials: Y
authors.lastname: Fu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qiu
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Fu
authors.forename: Yuzhang
authors.initials: Y
authors.lastname: Wu
authors.forename: Wenyue
authors.initials: W
authors.lastname: Xu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008288:Malaria / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000097:blood / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010967:Plasmodium yoelii / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D044087:Receptor, Anaphylatoxin C5a / Q000097:blood / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000097:blood
chemical_list: D017780:Malaria Vaccines; D044087:Receptor, Anaphylatoxin C5a; D015164:Vaccines, Inactivated