RESUMO
Programmed death-1 ligand 1 (PD-L1) is a coinhibitory molecule that negatively regulates multiple tolerance checkpoints. In the NOD mouse model, PD-L1 regulates the development of diabetes. PD-L1 has two binding partners, programmed death-1 and B7-1, but the significance of the PD-L1:B7-1 interaction in regulating self-reactive T cell responses is not yet clear. To investigate this issue in NOD mice, we have compared the effects of two anti-PD-L1 Abs that have different blocking activities. Anti-PD-L1 mAb 10F.2H11 sterically and functionally blocks only PD-L1:B7-1 interactions, whereas anti-PD-L1 mAb 10F.9G2 blocks both PD-L1:B7-1 and PD-L1:programmed death-1 interactions. Both Abs had potent, yet distinct effects in accelerating diabetes in NOD mice: the single-blocker 10F.2H11 mAb was more effective at precipitating diabetes in older (13-wk-old) than in younger (6- to 7-wk-old) mice, whereas the dual-blocker 10F.9G2 mAb rapidly induced diabetes in NOD mice of both ages. Similarly, 10F.2H11 accelerated diabetes in recipients of T cells from diabetic, but not prediabetic mice, whereas 10F.9G2 was effective in both settings. Both anti-PD-L1 mAbs precipitated diabetes in adoptive transfer models of CD4(+) and CD8(+) T cell-driven diabetes. Taken together, these data demonstrate that the PD-L1:B7-1 pathway inhibits potentially pathogenic self-reactive effector CD4(+) and CD8(+) T cell responses in vivo, and suggest that the immunoinhibitory functions of this pathway may be particularly important during the later phases of diabetogenesis.
Assuntos
Antígeno B7-1/fisiologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Inibidores do Crescimento/fisiologia , Glicoproteínas de Membrana/fisiologia , Peptídeos/fisiologia , Transdução de Sinais/imunologia , Transferência Adotiva , Animais , Anticorpos Bloqueadores/administração & dosagem , Antígenos CD/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Antígeno B7-H1 , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Diabetes Mellitus Tipo 1/genética , Feminino , Ligantes , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Peptídeos/deficiência , Peptídeos/imunologia , Receptor de Morte Celular Programada 1 , Ligação Proteica/imunologia , Transdução de Sinais/genéticaRESUMO
The PD-1 pathway regulates dysfunctional T cells in chronic infection and cancer, but the role of this pathway during acute infection remains less clear. Here, we demonstrate that PD-1 signals are needed for optimal memory. Mice deficient in the PD-1 pathway exhibit impaired CD8+ T cell memory following acute influenza infection, including reduced virus-specific CD8+ T cell numbers and compromised recall responses. PD-1 blockade during priming leads to similar differences early post-infection but without the defect in memory formation, suggesting that timing and/or duration of PD-1 blockade could be tailored to modulate host responses. Our studies reveal a role for PD-1 as an integrator of CD8+ T cell signals that promotes CD8+ T cell memory formation and suggest PD-1 continues to fine-tune CD8+ T cells after they migrate into non-lymphoid tissues. These findings have important implications for PD-1-based immunotherapy, in which PD-1 inhibition may influence memory responses in patients.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Vírus da Influenza A Subtipo H3N2/fisiologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais , Administração Intranasal , Animais , Morte Celular/imunologia , Diferenciação Celular/imunologia , Proliferação de Células , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/patologia , Especificidade da EspécieRESUMO
CD160 promotes NK cell cytotoxicity and IFN-γ production, but the function of CD160 on CD8+ T cells remains unclear with some studies supporting a coinhibitory role and others a costimulatory role. In this study, we demonstrate that CD160 has a costimulatory role in promoting CD8+ T cell effector functions needed for optimal clearance of oral Listeria monocytogenes infection. CD160-/- mice did not clear oral L. monocytogenes as efficiently as wild type (WT) littermates. WT RAG-/- and CD160-/- RAG-/- mice similarly cleared L. monocytogenes, indicating that CD160 on NK cells does not contribute to impaired L. monocytogenes clearance. Defective L. monocytogenes clearance is due to compromised intraepithelial lymphocytes and CD8+ T cell functions. There was a reduction in the frequencies of granzyme B-expressing intraepithelial lymphocytes in L. monocytogenes-infected CD160-/- mice as compared with WT littermate controls. Similarly, the frequencies of granzyme B-expressing splenic CD8+ T cells and IFN-γ and TNF-α double-producer CD8+ T cells were significantly reduced in L. monocytogenes-infected CD160-/- mice compared with WT littermates. Adoptive transfer studies showed that RAG-/- recipients receiving CD160-/- CD8+ T cells had a higher mortality, exhibited more weight loss, and had a higher bacterial burden compared with RAG-/- recipients receiving WT CD8+ T cells. These findings demonstrate that CD160 provides costimulatory signals to CD8+ T cells needed for optimal CD8+ T cell responses and protective immunity during an acute mucosal bacterial infection.
Assuntos
Antígenos CD/imunologia , Linfócitos T CD8-Positivos/imunologia , Listeria monocytogenes/imunologia , Microbiota/imunologia , Receptores Imunológicos/imunologia , Animais , Antígenos CD/biossíntese , Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Proteínas Ligadas por GPI/biossíntese , Proteínas Ligadas por GPI/deficiência , Proteínas Ligadas por GPI/imunologia , Imunidade nas Mucosas/imunologia , Listeriose/imunologia , Listeriose/prevenção & controle , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores Imunológicos/biossíntese , Receptores Imunológicos/deficiência , Baço/imunologiaRESUMO
While the role of PD-1 in inhibiting immunity during chronic infections is well established, its functions during acute infections are much less clear. The PD-1 pathway can dampen CD8 T cell responses during some acute infections and restrain responses by 'helpless' CD8 memory T cells. An emerging role for PD-1 in innate immunity has been revealed by recent studies showing that PD-1 can limit function of DC and macrophages as well as T cell independent B cell responses. Thus, PD-1 can influence adaptive immune responses during acute infections, though precisely how this regulation occurs is only just beginning to be appreciated.
Assuntos
Antígenos de Diferenciação/metabolismo , Regulação da Expressão Gênica/imunologia , Infecções/imunologia , Doença Aguda , Animais , Diferenciação Celular , Humanos , Memória Imunológica , Infecções/etiologia , Infecções/metabolismo , Ativação Linfocitária , Camundongos , Receptor de Morte Celular Programada 1 , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Both the programmed death (PD) 1-PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role in regulating induced T reg (iT reg) cell development and sustaining iT reg cell function. PD-L1(-/-) antigen-presenting cells minimally convert naive CD4 T cells to iT reg cells, showing the essential role of PD-L1 for iT reg cell induction. PD-L1-coated beads induce iT reg cells in vitro, indicating that PD-L1 itself regulates iT reg cell development. Furthermore, PD-L1 enhances and sustains Foxp3 expression and the suppressive function of iT reg cells. The obligatory role for PD-L1 in controlling iT reg cell development and function in vivo is illustrated by a marked reduction in iT reg cell conversion and rapid onset of a fatal inflammatory phenotype in PD-L1(-/-)PD-L2(-/-) Rag(-/-) recipients of naive CD4 T cells. PD-L1 iT reg cell development is mediated through the down-regulation of phospho-Akt, mTOR, S6, and ERK2 and concomitant with the up-regulation of PTEN, all key signaling molecules which are critical for iT reg cell development. Thus, PD-L1 can inhibit T cell responses by promoting both the induction and maintenance of iT reg cells. These studies define a novel mechanism for iT reg cell development and function, as well as a new strategy for controlling T reg cell plasticity.