ICOS is critical for T helper cell-mediated lung mucosal inflammatory responses.
We examined the requirement for and cooperation between CD28 and inducible costimulator (ICOS) in effective T helper (TH) cell responses in vivo. We found that both CD28 and ICOS were critical in determining the outcome of an immune response; cytolytic T lymphocyte-associated antigen 4-immunoglobulin (CTLA-4-Ig), ICOS-Ig and/or a neutralizing ICOS monoclonal antibody attenuated T cell expansion, TH2 cytokine production and eosinophilic inflammation. CD28-dependent signaling was essential during priming, whereas ICOS-B7RP-1 regulated TH effector responses, and the up-regulation of chemokine receptors that determine T cell migration. Our data suggests a scenario whereby both molecules regulate the outcome of the immune response but play separate key roles: CD28 primes T cells and ICOS regulates effector responses.
Gonzalo
J A
JA
Department of Biology, Inflammation Division, Millennium Pharmaceuticals Inc., 45-75 Sidney St., Cambridge, MA 02139, USA.
Tian
J
J
Delaney
T
T
Corcoran
J
J
Rottman
J B
JB
Lora
J
J
Al-garawi
A
A
Kroczek
R
R
Gutierrez-Ramos
J C
JC
Coyle
A J
AJ
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000235:genetics; D060908:CTLA-4 Antigen; D016207:Cytokines / Q000096:biosynthesis; D015870:Gene Expression; D018928:Immunity, Mucosal / Q000276:immunology; D018796:Immunoconjugates; D007073:Immunoglobulin E / Q000096:biosynthesis; D060889:Inducible T-Cell Co-Stimulator Protein; D008168:Lung / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D051381:Rats; D011921:Rats, Inbred WKY; D054397:Receptors, CCR3; D054398:Receptors, CCR4; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000235:genetics; D020545:Respiratory Mucosa / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; C515350:CCR3 protein, human; C515354:CCR4 protein, human; C103330:CCR8 protein, human; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C515351:Ccr3 protein, mouse; C515352:Ccr3 protein, rat; C515355:Ccr4 protein, mouse; C515356:Ccr4 protein, rat; C556707:Ctla4 protein, mouse; C556708:Ctla4 protein, rat; D016207:Cytokines; C556692:ICOS protein, human; C556694:Icos protein, mouse; C556695:Icos protein, rat; D018796:Immunoconjugates; D060889:Inducible T-Cell Co-Stimulator Protein; D054397:Receptors, CCR3; D054398:Receptors, CCR4; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D007073:Immunoglobulin E; D000069594:Abatacept