RESUMO
The prognosis of gliomas is generally poor since these tumors elude established therapeutic approaches. Immunotherapy might present an effective therapy in particular because the glioma cells are diffusely dispersed in the infiltration zone of the tumor and show a strong propensity to invade the surrounding brain along white matter tracts. Although various immune therapies for brain tumors are successful in rodents, there is currently no effective therapy in humans. In the present study, we investigated the mechanisms by which intracerebral IL-12 mediates rejection of GL261 cells in a syngenic mouse glioma model. Wild type mice revealed smaller tumors as compared to mice lacking functional T and B cells indicating that considerable immune dependent tumor rejection occurs physiologically in this model. However, glioma rejection was significantly enhanced in mice expressing IL-12 in the CNS and was predominantly dependent on the presence of CD8+ T cells while CD4+ T cells had less impact. Interestingly, the rejection of tumors was independent of IFN-gamma. Our findings contrast results obtained after in vitro or systemic stimulation with IL-12 and demonstrate that successful IL-12 induced glioma rejection critically depends on the localization, duration and time of IL-12 expression.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Glioma/imunologia , Interleucina-12/farmacologia , Animais , Linfócitos T CD4-Positivos/imunologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Imunoterapia/métodos , Interferon gama/imunologia , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Células Tumorais Cultivadas , Regulação para Cima/fisiologiaRESUMO
Highly differentiated CD8+CD28-CD27- T cells have short telomeres, defective telomerase activity, and reduced capacity for proliferation, indicating that they are close to replicative senescence. In addition, these cells express increased levels of the senescence-associated inhibitory receptor KLRG1 and have poor capacity for IL-2 synthesis and defective Akt (ser(473)) phosphorylation after activation. It is not known whether signaling via KLRG1 contributes to any of the attenuated differentiation-related functional changes in CD8+ T cells. To address this, we blocked KLRG1 signaling during T-cell receptor activation using antibodies against its major ligand, E-cadherin. This resulted in a significant enhancement of Akt (ser(473)) phosphorylation and T-cell receptor-induced proliferative activity of CD8+CD28-CD27- T cells. Furthermore, the increase of proliferation was directly linked to the Akt-mediated induction of cyclin D and E and reduction in the cyclin inhibitor p27 expression. In contrast, the reduced telomerase activity in highly differentiated CD8+CD28(-)CD27- T cells was not altered by KLRG1 blockade, indicating the involvement of other mechanisms. This is the first demonstration of a functional role for KLRG1 in primary human CD8+ T cells and highlights that certain functional defects that arise during progressive T-cell differentiation toward replicative senescence are maintained actively by inhibitory receptor signaling.