title: The inducible costimulator plays the major costimulatory role in humoral immune responses in the absence of CD28.
abstract: CD28 plays crucial costimulatory roles in T cell proliferation, cytokine production, and germinal center response. Mice that are deficient in the inducible costimulator (ICOS) also have defects in cytokine production and germinal center response. Because the full induction of ICOS in activated T cells depends on CD28 signal, the T cell costimulatory capacity of ICOS in the absence of CD28 has remained unclear. We have clarified this issue by comparing humoral immune responses in wild-type, CD28 knockout (CD28 KO), and CD28-ICOS double-knockout (DKO) mice. DKO mice had profound defects in Ab responses against environmental Ags, T-dependent protein Ags, and vesicular stomatitis virus that extended far beyond those observed in CD28 KO mice. However, DKO mice mounted normal Ab responses against a T-independent Ag, indicating that B cell function itself was normal. Restimulated CD4(+) DKO T cells that had been primed in vivo showed decreased proliferation and reduced IL-4 and IL-10 production compared with restimulated CD4(+) T cells from CD28 KO mice. Thus, in the absence of CD28, ICOS assumes the major T cell costimulatory role for humoral immune responses. Importantly, CD28-mediated ICOS up-regulation is not essential for ICOS function in vivo.
authors.affiliation: Advanced Medical Discovery Institute, Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Woong-Kyung
authors.initials: WK
authors.lastname: Suh
authors.forename: Anna
authors.initials: A
authors.lastname: Tafuri
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Berg-Brown
authors.forename: Arda
authors.initials: A
authors.lastname: Shahinian
authors.forename: Suzanne
authors.initials: S
authors.lastname: Plyte
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Duncan
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okada
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.forename: Bernhard
authors.initials: B
authors.lastname: Odermatt
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000502:physiology*; D018106:CD28 Antigens / Q000235:genetics* / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002999:Clone Cells; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D007070:Immunoglobulin A / Q000096:biosynthesis; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007074:Immunoglobulin G / Q000378:metabolism; D007075:Immunoglobulin M / Q000096:biosynthesis; D060889:Inducible T-Cell Co-Stimulator Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018353:Rhabdoviridae Infections / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D016207:Cytokines; C556694:Icos protein, mouse; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D060889:Inducible T-Cell Co-Stimulator Protein