Assuntos
Cromossomos Humanos Par 10/genética , Linfo-Histiocitose Hemofagocítica/história , Perforina/história , Citotoxicidade Imunológica/genética , História do Século XX , Humanos , Ativação Linfocitária/imunologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Macrófagos/imunologia , Perforina/genética , Linfócitos T Citotóxicos/química , Linfócitos T Citotóxicos/imunologiaRESUMO
Murine 2B4 (CD244) is a cell surface receptor expressed on all NK cells, gammadelta-T cells, a subset of CD8(+) T cells, and all CD14(+) monocytes. 2B4 binds to CD48 with high affinity, and cross-linking 2B4 with anti-2B4 Ab in vitro causes activation of NK cells. To study its physiological role, we have generated, by gene targeting, mice deficient in the expression of this cell surface molecule. The expression of lymphoid cell surface markers on PBMC and splenocytes of mice homozygous for the mutation in 2B4 (2B4(-/-)) is identical to that in wild-type mice. However, thymocytes from female 2B4(-/-) mice, but not male 2B4(-/-) mice, have an increase in the immature CD4(-)/CD8(-) population. To investigate the in vivo role of 2B4, wild-type and 2B4(-/-) mice were injected with CD48(+) and CD48(-) metastatic B16 melanoma cells. Wild-type mice rejected CD48(+) melanoma poorly compared with CD48(-) tumor cells, suggesting that ligation of 2B4 by CD48 on melanoma cells is inhibitory. In keeping with this, male 2B4(-/-) mice showed enhanced ability to reject CD48(+) melanoma cells. However, female 2B4(-/-) mice poorly rejected both CD48(+) and CD48(-) melanoma cells, revealing a gender-specific and CD48-independent defect in mice lacking 2B4. In vitro and in vivo experiments reveal a complex role of NK cells in gender specificity.
Assuntos
Antígenos CD/genética , Rejeição de Enxerto/genética , Rejeição de Enxerto/imunologia , Células Matadoras Naturais/imunologia , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Animais , Antígenos CD/metabolismo , Antígenos CD/fisiologia , Relação CD4-CD8 , Antígeno CD48 , Linhagem Celular , Linhagem Celular Tumoral , Cruzamentos Genéticos , Feminino , Marcação de Genes , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Masculino , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Imunológicos/biossíntese , Receptores Imunológicos/fisiologia , Caracteres Sexuais , Família de Moléculas de Sinalização da Ativação Linfocitária , TransfecçãoRESUMO
Natural killer (NK) cells are critical in the immune response to tumor cells, virally infected cells, and bone marrow allografts. 2B4 (CD244) is expressed on all NK cells and the ligand for 2B4, CD48, is expressed on hematopoietic cells. Cross-linking 2B4 on NK cells with anti-2B4 monoclonal antibody leads to NK cell activation in vitro. Therefore, 2B4 is considered to be an activating receptor. Surprisingly, we have found, using antibody-blocking and 2B4-deficient NK cells, that NK lysis of CD48(+) tumor and allogeneic targets is inhibited by 2B4 ligation. Interferon gamma production by NK cells is also inhibited. Using a peritoneal tumor clearance assay, it was found that 2B4(-/-) mice have increased clearance of CD48(+) tumor cells in vivo. Retroviral transduction of 2B4 was sufficient to restore inhibition in 2B4(-/-) primary NK cells. It was found that although mature NK cells express SH2D1A, in vitro-derived NK cells do not. However, both populations are inhibited by 2B4 ligation. This indicates that 2B4 inhibitory signaling occurs regardless of the presence of SH2D1A. These findings reveal a novel role for 2B4 as a non-major histocompatibility complex binding negative regulator of NK cells.
Assuntos
Antígenos CD/imunologia , Células Matadoras Naturais/imunologia , Complexo Principal de Histocompatibilidade , Glicoproteínas de Membrana/imunologia , Receptores Imunológicos/imunologia , Animais , Antígenos CD/genética , Antígeno CD48 , Citotoxicidade Imunológica/imunologia , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Família de Moléculas de Sinalização da Ativação LinfocitáriaRESUMO
CD8 T cells persist at high frequencies in peripheral organs after resolution of an immune response, and their presence in the periphery is important for resistance to secondary challenge. We show here that LCMV-specific T cells in peripheral tissue (peritoneal cavity, lung, fat pads) reacted much less with the apoptotic marker Annexin-V than those in spleen and lymph nodes. This was not due to a TCR-based selection. In comparison to lymphoid tissue, T cells in the periphery expressed lower levels of Fas and Fas ligand and were resistant to activation-induced cell death in vitro. This may contribute to the survival of nondividing peripheral memory T cells, enabling them to efficiently function without being driven into apoptosis.
Assuntos
Apoptose/imunologia , Infecções por Arenaviridae/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Vírus da Coriomeningite Linfocítica , Tecido Linfoide/imunologia , Animais , Anexina A5/metabolismo , Infecções por Arenaviridae/patologia , Sobrevivência Celular/imunologia , Camundongos , Especificidade de Órgãos/imunologiaAssuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Memória Imunológica , Animais , Antígenos CD , Glicoproteínas/genética , Glicoproteínas/imunologia , Humanos , Imunoglobulinas/genética , Imunoglobulinas/imunologia , Camundongos , Camundongos Knockout , Receptores de Superfície Celular , Membro 1 da Família de Moléculas de Sinalização da Ativação LinfocitáriaRESUMO
Viral infections induce first a loss and then an increase in natural killer (NK) and CD8(+) T cells. NK cells expressing Ly49G2 were selectively expanded by several viruses and poly I:C. CD8(+) T cells expressing Ly49G2 were selectively expanded by poly I:C and participated in the antigen-specific response to lymphocytic choriomeningitis virus.
