RESUMO
Despite their increasing use in autoimmune, inflammatory, and allergic conditions, the mechanism of action of i.v. Igs (IVIg) is poorly understood. On the basis of the critical role of invariant NKT (iNKT) cells in allergic airway inflammation (AAI) and their constitutive expression of the low-affinity IgG receptor FcγRIIIA, we surmised that IVIg targets iNKT cells to exert their anti-inflammatory effect. We found that IVIg treatment significantly inhibited AAI in OVA-sensitized C57BL/6 mice and downregulated α-galactosylceramide-induced iNKT cell activation and cytokine production. Allergic responses were restored in iNKT cell-deficient mice by transferring iNKT cells from PBS- but not from IVIg-treated mice, suggesting that IVIg acts directly on activated iNKT cells that have a critical role in AAI. The inhibitory effects of IVIg on both iNKT cell activation/function and OVA-driven AAI were lost in FcγRIIIA(-/-) mice. Our data unravel an FcγRIIIA-dependent inhibitory effect of IVIg on activated iNKT cells that confers protection in AAI.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Imunoglobulinas Intravenosas/fisiologia , Mediadores da Inflamação/fisiologia , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia , Receptores de IgG/fisiologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/prevenção & controle , Transferência Adotiva , Alérgenos/imunologia , Alérgenos/toxicidade , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Hiper-Reatividade Brônquica/terapia , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Galactosilceramidas/antagonistas & inibidores , Galactosilceramidas/farmacologia , Imunoglobulinas Intravenosas/uso terapêutico , Mediadores da Inflamação/uso terapêutico , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/metabolismo , Ovalbumina/imunologia , Ovalbumina/toxicidade , Receptores de IgG/uso terapêutico , Hipersensibilidade Respiratória/patologia , Baço/imunologia , Baço/patologia , Baço/transplanteRESUMO
Activation of invariant natural killer T (iNKT) cells by treatment with their α-galactosyl ceramide ligand provides therapeutic benefits in several immune inflammatory settings. Given the artificial nature of this stimulation, the natural regulatory functions of iNKT remain uncertain. Addressing this issue in a mouse model of innate-cell-driven lung inflammation induced by the cytokine/alarmin IL-33 that targets iNKT cells, we found that eosinophil and neutrophil recruitment was markedly increased in treated iNKT cell-deficient (Jα18 KO) mice, as was the local production of eotaxin and keratinocyte chemoattractant chemokines. By contrast, lung inflammation decreased after adoptive transfer of iNKT cells, which restored the WT inflammatory response in Jα18 KO mice. Finally, we established that this natural anti-inflammatory function of iNKT cells depends on their IFN-γ production and on endogenous IL-12. Our study provides the first evidence of a protective role of iNKT cells during lung inflammation that does not require pharmacological TCR engagement.