RESUMEN
The T cell costimulatory molecule CD28 plays an important role in the thymic generation of Foxp3(+) regulatory T cells (Tregs) essential for the maintenance of self-tolerance. In this study, we show that a cell-intrinsic signal from CD28 is involved in the generation of cytokine-responsive Foxp3(-) precursors using studies of mixed bone marrow chimeras as well as TCR-specific generation of Foxp3(+) cells using intrathymic transfer of TCR-transgenic thymocytes expressing a natural Treg TCR. Contrary to a previous report, the analysis of CD28 mutant knockin mice revealed that this cell-intrinsic signal is only partially dependent on the Lck-binding PYAP motif. Surprisingly, even though the absence of CD28 resulted in a 6-fold decrease in thymic Tregs, the TCR repertoires of CD28-deficient and sufficient cells were largely overlapping. Thus, these data suggest that CD28 does not operate by markedly enlarging the repertoire of TCRs available for Treg development, but rather by improving the efficiency of Treg development of thymocytes expressing natural Treg TCRs.
Asunto(s)
Antígenos CD28/inmunología , Diferenciación Celular/inmunología , Células Precursoras de Linfocitos T/citología , Subgrupos de Linfocitos T/citología , Linfocitos T Reguladores/citología , Animales , Antígenos CD28/metabolismo , Separación Celular , Citocinas/inmunología , Citocinas/metabolismo , Citometría de Flujo , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Técnicas de Sustitución del Gen , Ratones , Ratones Endogámicos C57BL , Células Precursoras de Linfocitos T/inmunología , Células Precursoras de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
Pancreatic adenocarcinoma is the fourth leading cause of cancer death with an overall 5-year survival of less than 5%. As there is ample evidence that pancreatic adenocarcinomas elicit antitumor immune responses, identification of pancreatic cancer-associated antigens has spurred the development of vaccination-based strategies for treatment. While promising results have been observed in animal tumor models, most clinical studies have found only limited success. As most trials were performed in patients with advanced pancreatic cancer, the contribution of immune suppressor mechanisms should be taken into account. In this article, we detail recent work in tumor antigen vaccination and the recently identified mechanisms of immune suppression in pancreatic cancer. We offer our perspective on how to increase the clinical efficacy of vaccines for pancreatic cancer.
Asunto(s)
Adenocarcinoma/terapia , Antígenos de Neoplasias/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Inmunoterapia/métodos , Neoplasias Pancreáticas/terapia , Receptores de Antígenos/uso terapéutico , Adenocarcinoma/inmunología , Animales , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/clasificación , Vacunas contra el Cáncer/inmunología , Ensayos Clínicos como Asunto , Humanos , Terapia de Inmunosupresión , Ratones , Neoplasias Pancreáticas/inmunología , Receptores de Antígenos/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/uso terapéutico , Resultado del Tratamiento , VacunaciónRESUMEN
Despite extensive study, the role of phosphatidylinositol 3-kinase (PI3-kinase) activation in CD28 function has been highly contentious. To definitively address this question, we generated knock-in mice expressing mutations in two critical domains of the cytoplasmic tail of CD28. Mutation of the proximal tyrosine motif interrupted PI3-kinase binding and prevented CD28-dependent phosphorylation of protein kinase B (PKB)/Akt; however, there was no detectable effect on interleukin-2 (IL-2) secretion, expression of Bcl-X(L), or on T-cell function in vivo. Furthermore, we demonstrate that signaling initiated by the C-terminal proline motif is directly responsible for tyrosine phosphorylation of phosphoinosotide-dependent kinase 1, protein kinase C theta, and glycogen synthase kinase 3beta, as well as contributing to threonine phosphorylation of PKB. T cells mutated in this domain were profoundly impaired in IL-2 secretion, and the mice had marked impairment of humoral responses as well as less severe disease manifestations in experimental allergic encephalomyelitis. These data demonstrate that the distal proline motif initiates a critical nonredundant signaling pathway, whereas direct activation of PI3-kinase by the proximal tyrosine motif of CD28 is not required for normal T-cell function.