RESUMO
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.
Assuntos
Anticorpos Antivirais/biossíntese , Antígenos de Diferenciação de Linfócitos T/fisiologia , Antígenos CD28/genética , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos CD28/fisiologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Divisão Celular/genética , Divisão Celular/imunologia , Células Clonais , Cruzamentos Genéticos , Citocinas/biossíntese , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Imunoglobulina A/biossíntese , Switching de Imunoglobulina/genética , Imunoglobulina G/metabolismo , Imunoglobulina M/biossíntese , Proteína Coestimuladora de Linfócitos T Induzíveis , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Rhabdoviridae/genética , Infecções por Rhabdoviridae/imunologia , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/patologia , Vírus da Estomatite Vesicular Indiana/imunologiaRESUMO
We investigated the in vivo function of the B7 family member B7-H3 (also known as B7RP-2) by gene targeting. B7-H3 inhibited T cell proliferation mediated by antibody to T cell receptor or allogeneic antigen-presenting cells. B7-H3-deficient mice developed more severe airway inflammation than did wild-type mice in conditions in which T helper cells differentiated toward type 1 (T(H)1) rather than type 2 (T(H)2). B7-H3 expression was consistently enhanced by interferon-gamma but suppressed by interleukin 4 in dendritic cells. B7-H3-deficient mice developed experimental autoimmune encephalomyelitis several days earlier than their wild-type littermates, and accumulated higher concentrations of autoantibodies to DNA. Thus, B7-H3 is a negative regulator that preferentially affects T(H)1 responses.