RESUMEN
The inducible co-stimulatory molecule (ICOS) is a CD28 homologue implicated in regulating T-cell differentiation. Because co-stimulatory signals are critical for regulating T-cell activation, an understanding of co-stimulatory signals may enable the design of rational therapies for immune-mediated diseases. According to the two-signal model for T-cell activation, T cells require an antigen-specific signal and a second, co-stimulatory, signal for optimal T-cell activation. The co-stimulatory signal promotes T-cell proliferation, lymphokine secretion and effector function. The B7-CD28 pathway provides essential signals for T-cell activation, but does not account for all co-stimulation. We have generated mice lacking ICOS (ICOS-/- ) to determine the essential functions of ICOS. Here we report that ICOS-/- mice exhibit profound deficits in immunoglobulin isotype class switching, accompanied by impaired germinal centre formation. Class switching was restored in ICOS-/- mice by CD40 stimulation, showing that ICOS promotes T-cell/B-cell collaboration through the CD40/CD40L pathway.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/fisiología , Antígenos CD40/fisiología , Cambio de Clase de Inmunoglobulina , Animales , Formación de Anticuerpos , Antígenos de Diferenciación de Linfocitos T/genética , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Ligando de CD40/fisiología , Marcación de Gen , Centro Germinal/fisiología , Haptenos , Hemocianinas/inmunología , Isotipos de Inmunoglobulinas , Proteína Coestimuladora de Linfocitos T Inducibles , Ratones , Linfocitos T/inmunologíaRESUMEN
Programmed death I (PD-I)-deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identify here PD-1 ligand 2 (PD-L2) as a second ligand for PD-1 and compare the function and expression of PD-L1 and PD-L2. Engagement of PD-1 by PD-L2 dramatically inhibits T cell receptor (TCR)-mediated proliferation and cytokine production by CD4+ T cells. At low antigen concentrations, PD-L2-PD-1 interactions inhibit strong B7-CD28 signals. In contrast, at high antigen concentrations, PD-L2-PD-1 interactions reduce cytokine production but do not inhibit T cell proliferation. PD-L-PD-1 interactions lead to cell cycle arrest in G0/G1 but do not increase cell death. In addition, ligation of PD-1 + TCR leads to rapid phosphorylation of SHP-2, as compared to TCR ligation alone. PD-L expression was up-regulated on antigen-presenting cells by interferon gamma treatment and was also present on some normal tissues and tumor cell lines. Taken together, these studies show overlapping functions of PD-L1 and PD-L2 and indicate a key role for the PD-L-PD-1 pathway in regulatingT cell responses.
Asunto(s)
Antígenos de Superficie/inmunología , Antígeno B7-1 , Proteínas Sanguíneas , Activación de Linfocitos , Péptidos/inmunología , Linfocitos T/inmunología , Secuencia de Aminoácidos , Animales , Antígenos CD , Apoptosis , Proteínas Reguladoras de la Apoptosis , Antígeno B7-H1 , Antígenos CD28/inmunología , Células CHO , Células Cultivadas , Cricetinae , Citocinas/biosíntesis , Humanos , Péptidos y Proteínas de Señalización Intercelular , Células Jurkat , Ligandos , Glicoproteínas de Membrana , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Péptidos/genética , Péptidos/metabolismo , Proteína 2 Ligando de Muerte Celular Programada 1 , Receptor de Muerte Celular Programada 1 , Receptores de Antígenos de Linfocitos T/inmunología , Homología de Secuencia de Aminoácido , TransfecciónRESUMEN
The inducible costimulatory (ICOS) molecule is expressed by activated T cells and has homology to CD28 and CD152. ICOS binds B7h, a molecule expressed by APC with homology to CD80 and CD86. To investigate regulation of ICOS expression and its role in Th responses we developed anti-mouse ICOS mAbs and ICOS-Ig fusion protein. Little ICOS is expressed by freshly isolated mouse T cells, but ICOS is rapidly up-regulated on most CD4(+) and CD8(+) T cells following stimulation of the TCR. Strikingly, ICOS up-regulation is significantly reduced in the absence of CD80 and CD86 and can be restored by CD28 stimulation, suggesting that CD28-CD80/CD86 interactions may optimize ICOS expression. Interestingly, TCR-transgenic T cells differentiated into Th2 expressed significantly more ICOS than cells differentiated into Th1. We used two methods to investigate the role of ICOS in activation of CD4(+) T cells. First, CD4(+) cells were stimulated with beads coated with anti-CD3 and either B7h-Ig fusion protein or control Ig fusion protein. ICOS stimulation enhanced proliferation of CD4(+) cells and production of IFN-gamma, IL-4, and IL-10, but not IL-2. Second, TCR-transgenic CD4(+) T cells were stimulated with peptide and APC in the presence of ICOS-Ig or control Ig. When the ICOS:B7h interaction was blocked by ICOS-Ig, CD4(+) T cells produced more IFN-gamma and less IL-4 and IL-10 than CD4(+) cells differentiated with control Ig. These results demonstrate that ICOS stimulation is important in T cell activation and that ICOS may have a particularly important role in development of Th2 cells.
Asunto(s)
Adyuvantes Inmunológicos/fisiología , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Antígenos CD28/fisiología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Animales , Antígenos de Diferenciación de Linfocitos T/inmunología , Antígenos de Diferenciación de Linfocitos T/metabolismo , Antígenos de Diferenciación de Linfocitos T/fisiología , Unión Competitiva/genética , Unión Competitiva/inmunología , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular/inmunología , Citocinas/biosíntesis , Inmunoglobulinas/genética , Inmunoglobulinas/metabolismo , Inmunoglobulinas/farmacología , Ligando Coestimulador de Linfocitos T Inducibles , Proteína Coestimuladora de Linfocitos T Inducibles , Ligandos , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Proteínas/genética , Proteínas/metabolismo , Proteínas/farmacología , Proteínas/fisiología , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Células TH1/inmunología , Células TH1/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Regulación hacia Arriba/inmunologíaRESUMEN
PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon gamma, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.