RESUMO
ULBPs are human ligands for NKG2D, an activating receptor expressed on natural killer (NK) cells, NK1.1(+) T cells, and T cells. ULBPs are expressed by a variety of leukemias, carcinomas, melanomas, and tumor cell lines. ULBP expression correlates with improved survival in cancer patients, however, the nature of the immune response that ULBPs elicit is not well understood. We report that ectopic expression of ULBP1 or ULBP2 on murine EL4 or RMA tumor cells elicits potent antitumor responses in syngeneic C57BL/6 and SCID mice. Although binding of ULBP3 to murine NKG2D could not be demonstrated in vitro, ULBP3 can also stimulate antitumor responses, suggesting that ULBP3 binds to murine NKG2D or possibly another receptor in vivo. ULBP expression was found to recruit NK cells, NK1.1(+) T cells, and T cells to the tumor. IL-15 was found to strongly enhance the immune response directed against ULBP-expressing tumors. Tumors can evade NKG2D immunity by down-regulating expression of NKG2D. Our data suggest that IL-15 may be useful for overcoming this tumor-evasion strategy. Together, these results demonstrate that ULBP expression can elicit a potent immune response and suggest that ULBPs, alone or in combination with IL-15, can be exploited for antitumor therapy.
Assuntos
Proteínas de Transporte/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Interleucina-15/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Receptores Imunológicos/imunologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/uso terapêutico , Linhagem Celular Tumoral , Proteínas Ligadas por GPI , Regulação Neoplásica da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/uso terapêutico , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Peptídeos e Proteínas de Sinalização Intracelular , Células Matadoras Naturais/imunologia , Ligantes , Proteínas de Membrana , Camundongos , Camundongos SCID , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/terapia , Receptores Imunológicos/genética , Receptores de Células Matadoras Naturais , Linfócitos T/imunologia , Evasão Tumoral/genética , Evasão Tumoral/imunologiaRESUMO
BACKGROUND: Respiratory tract dendritic cells (DCs) are crucial for the regulation of immune responses to inhaled antigens. However, the precise function of the multiple DC subsets present in the lungs and the lung-draining lymph nodes is unknown. Fms-like tyrosine kinase 3 ligand (FLT3L) is a hematopoietic growth factor that drives the development of multiple subsets of DCs in the lymphoid organs. OBJECTIVE: We sought to study the contribution of DC subsets in the regulation of the balance between tolerance and immunity against respiratory antigens by using FLT3L knockout mice. METHODS: Phenotypic analysis of DC subsets in the airways and lungs of FLT3L knockout mice was performed. By using various experimental models, the role of FLT3L-dependent DCs in the priming of naive T cells, the presentation of inhaled antigen to previously primed T H 2 cells, and intranasal tolerance induction was addressed. RESULTS: FLT3L knockout mice display a 90% reduction in lung parenchyma DCs but a normal number of airway DCs and blood monocytes. FLT3L knockout mice had a normal induction of eosinophilic inflammation in response to intranasal administration of allergen. FLT3L-dependent DCs were not required for the presentation of inhaled antigen to previously primed T H 2 cells, and normal induction of T-cell tolerance in response to inhaled antigen was observed in FLT3L knockout mice. CONCLUSION: Airway DC development is independent of FLT3L. FLT3L-dependent DCs are not required for the development and maintenance of airway inflammation or for the induction of intranasal tolerance. Our results point to airway DCs as the major regulators of the balance between tolerance and immunity to inhaled antigens.
Assuntos
Alérgenos/administração & dosagem , Células Dendríticas/imunologia , Hipersensibilidade/imunologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/deficiência , Administração por Inalação , Alérgenos/efeitos adversos , Animais , Apresentação de Antígeno , Antígenos de Plantas , Modelos Animais de Doenças , Feminino , Hipersensibilidade/sangue , Hipersensibilidade/etiologia , Tolerância Imunológica , Pulmão/imunologia , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Sistema Respiratório/imunologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
The putative counterparts of human plasmacytoid pre-dendritic cells (pDCs) have been described in vivo in mouse models and very recently in an in vitro culture system. In this study, we report that large numbers of bone marrow-derived murine CD11c(+)B220(+) pDCs can be generated with Flt3 ligand (FL) as the sole exogenous differentiation/growth factor and that pDC generation is regulated in vivo by FL because FL-deficient mice showed a major reduction in splenic pDC numbers. We extensively analyzed bone marrow-derived CD11c(+)B220(+) pDCs and described their immature APC phenotype based on MHC class II, activation markers, and chemokine receptor level of expression. CD11c(+)B220(+) pDCs showed a nonoverlapping Toll-like receptor pattern of expression distinct from that of classical CD11c(+)B220(-) dendritic cells and were poor T cell stimulators. Stimulation of CD11c(+)B220(+) pDCs with oligodeoxynucleotides containing certain CpG motifs plus CD40 ligand plus GM-CSF led to increased MHC class II, CD80, CD86, and CD8alpha expression levels, to a switch in chemokine receptor expression that affected their migration, to IFN-alpha and IL-12 secretion, and to the acquisition of priming capacities for both CD4(+) and CD8(+) OVA-specific TCR-transgenic naive T cells. Thus, the in vitro generation of murine pDCs may serve as a useful tool to further investigate pDC biology as well as the potential role of these cells in viral immunity and other settings.