RESUMO
The co-engagement of fragment crystallizable (Fc) gamma receptors (FcγRs) with the Fc region of recombinant immunoglobulin monoclonal antibodies (mAbs) and its contribution to therapeutic activity has been extensively studied. For example, Fc-FcγR interactions have been shown to be important for mAb-directed effector cell activities, as well as mAb-dependent forward signaling into target cells via receptor clustering. Here we identify a function of mAbs targeting T cell-expressed antigens that involves FcγR co-engagement on antigen-presenting cells (APCs). In the case of mAbs targeting CTLA-4 and TIGIT, the interaction with FcγR on APCs enhanced antigen-specific T cell responses and tumoricidal activity. This mechanism extended to an anti-CD45RB mAb, which led to FcγR-dependent regulatory T cell expansion in mice.
Assuntos
Anticorpos Monoclonais/imunologia , Células Apresentadoras de Antígenos/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Receptores de IgG/imunologia , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/uso terapêutico , Células Apresentadoras de Antígenos/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Ligação Proteica , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de IgG/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Interferon regulatory factor (IRF) 5 is a key transcription factor for the activation of innate immune responses downstream of Toll-like receptor signaling. Based on recent genetic analyses, IRF5 is a focus for its potential involvement in systemic lupus erythematosus (SLE), although how IRF5 contributes to SLE is uncertain. In this study, we demonstrate a requirement for IRF5 in the development of murine SLE via its role in B lymphocytes. We show that antinuclear autoantibodies and Ig glomerular deposits, hallmarks of SLE, are absent in Irf5(-/-) mice challenged to develop SLE by pristane injection. In particular, production of autoantibodies of the IgG2a subtype, the most prominent isotype in inducing autoimmunity, requires IRF5. Finally, we provide evidence for the critical role of this transcription factor in the secretion of pathogenic antibodies through its direct control of class switch recombination of the gamma2a locus. By demonstrating a B-cell-intrinsic role, this study places IRF5 in a context that may have implications for understanding the pathogenesis of human SLE.