The inducible costimulator plays the major costimulatory role in humoral immune responses in the absence of CD28.
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.
Suh
Woong-Kyung
WK
Advanced Medical Discovery Institute, Ontario Cancer Institute, Toronto, Ontario, Canada.
Tafuri
Anna
A
Berg-Brown
Nancy N
NN
Shahinian
Arda
A
Plyte
Suzanne
S
Duncan
Gordon S
GS
Okada
Hitoshi
H
Wakeham
Andrew
A
Odermatt
Bernhard
B
Ohashi
Pamela S
PS
Mak
Tak W
TW
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
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