RESUMO
In these studies, we examined the effects of OX40 ligand (OX40L) deficiency on the development of Th2 cells during the Th2 immune response to the intestinal nematode parasite Heligmosomoides polygyrus. Elevations in IL-4 production and total and Ag-specific serum IgE levels were partially inhibited during both the primary and memory immune responses to H. polygyrus in OX40L(-/-) mice. The host-protective memory response was compromised in OX40L(-/-) mice, as decreased worm expulsion and increased egg production were observed compared with H. polygyrus-inoculated OX40L(+/+) mice. To further examine the nature of the IL-4 defect during priming, adoptively transferred DO11.10 T cells were analyzed in the context of the H. polygyrus response. Although Ag-specific T cell IL-4 production was reduced in the OX40L(-/-) mice following immunization with OVA peptide plus H. polygyrus, Ag-specific T cell expansion, cell cycle progression, CXCR5 expression, and migration were comparable between OX40L(+/+) and OX40L(-/-) mice inoculated with OVA and H. polygyrus. These studies suggest an important role for OX40/OX40L interactions in specifically promoting IL-4 production, as well as associated IgE elevations, in Th2 responses to H. polygyrus. However, OX40L interactions were not required for serum IgG1 elevations, increases in germinal center formation, and Ag-specific Th2 cell expansion and migration to the B cell zone.
Assuntos
Enteropatias Parasitárias/imunologia , Glicoproteínas de Membrana/fisiologia , Nematospiroides dubius/imunologia , Receptores do Fator de Necrose Tumoral , Infecções por Strongylida/imunologia , Células Th2/imunologia , Células Th2/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Sequência de Aminoácidos , Animais , Antígenos de Helmintos/imunologia , Subpopulações de Linfócitos B/imunologia , Ciclo Celular/genética , Ciclo Celular/imunologia , Movimento Celular/genética , Movimento Celular/imunologia , Quimiocinas CXC/metabolismo , Epitopos de Linfócito T/imunologia , Centro Germinativo/imunologia , Centro Germinativo/patologia , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Imunidade Inata/genética , Imunização Secundária , Imunoglobulina E/biossíntese , Imunoglobulina E/sangue , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Injeções Subcutâneas , Interleucina-4/antagonistas & inibidores , Interleucina-4/biossíntese , Enteropatias Parasitárias/genética , Ligantes , Linfonodos/imunologia , Linfonodos/patologia , Ativação Linfocitária/genética , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Pescoço , Ligante OX40 , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Receptores CXCR5 , Receptores de Quimiocinas , Receptores de Citocinas/biossíntese , Receptores OX40 , Infecções por Strongylida/genética , Células Th2/patologia , Fatores de Necrose Tumoral , Regulação para Cima/genéticaRESUMO
Th2 immune responses to a number of infectious pathogens are dependent on B7-1/B7-2 costimulatory molecule interactions. We have now examined the Th2 immune response to Nippostrongylus brasiliensis (Nb) in B7-1/B7-2(-/-) mice and show that Th2 effector cells develop that can mediate worm expulsion and produce substantial Th2 cytokines comparable with wild-type infected mice; however, in marked contrast, B cell Ag-specific Ab production is abrogated after B7 blockade. To examine the mechanism of T cell activation, OVA-specific DO11.10 T cells were transferred to recipient mice, which were then immunized with a combination of Nb plus OVA or either alone. Only the combination of Nb plus OVA triggered T cell differentiation to OVA-specific Th2 cells, suggesting that Nb acts as an adjuvant to stimulate Ag-specific naive T cells to differentiate to effector Th2 cells. Furthermore, using the DO11.10 TCR-transgenic T cell adoptive transfer model, we show that blocking B7-1/B7-2 interactions does not impair nonparasite Ag-specific DO11.10 Th2 cell differentiation; however, DO11.10 T cell cycle progression and migration to the B cell zone are inhibited.
