Costimulator B7-DC attenuates strong Th2 responses induced by Nippostrongylus brasiliensis.
The caliber and magnitude of T cell responses are regulated by costimulatory molecules following the engagement of TCRs and MHC molecules. B7-DC has the highest homology with B7-H1 in the B7 family, and both of them bind an immunoregulatory molecule, programmed death 1. Previous studies have demonstrated that B7-DC stimulates T cell proliferation and CTL generation, which sharply contrasts the inhibitory role of B7-H1. Th2 cytokines prompt B7-DC expression, which in turn enhances Th1 responses. In this study, we used an intestinal nematode, Nippostrongylus brasiliensis, to induce strong Th2 responses and to evaluate B7-DC function under Th2-polarizing conditions in vivo. By either blocking B7-DC expression during N. brasiliensis infection or by examining N. brasiliensis-infected B7-DC knockout mice, we observed enhanced eosinophilia, the overproduction of serum IgE, and increased Th2 cytokine production along with decreased Th1 cytokine production (particularly IFN-gamma production), indicating that B7-DC inhibits Th2 responses. Our results further demonstrate that the inhibition of Th2 responses by B7-DC occurs independently of programmed death 1 but conceivably acts through an as yet unknown alternative receptor that enhances Th1 responses. Although the deficiency of B7-DC expression that enhanced the production of IL-13 paradoxically resulted in better protection against N. brasiliensis infection, our results show that B7-DC plays an important role in bolstering a robust Th1 response that is required for effective antiviral and anticancer immunity, even under a strong Th2-polarizing environment induced by N. brasiliensis infection.
Ishiwata
Kenji
K
Department of Tropical Medicine, Jikei University School of Medicine, Tokyo, Japan.
Watanabe
Naohiro
N
Guo
Miao
M
Tomihara
Kei
K
Brumlik
Michael J
MJ
Yagita
Hideo
H
Pardoll
Drew
D
Chen
Lieping
L
Shin
Tahiro
T
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004802:Eosinophilia / Q000276:immunology / Q000469:parasitology; D025461:Feedback, Physiological; D007073:Immunoglobulin E / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009559:Nippostrongylus / Q000276:immunology*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D017206:Strongylida Infections / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology
D018122:B7-1 Antigen; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; D007073:Immunoglobulin E