RESUMO
SUMMARY: After binding its natural ligand cluster of differentiation 70 (CD70), CD27, a tumor necrosis factor receptor (TNFR)-associated factor-binding member of the TNFR family, regulates cellular activity in subsets of T, B, and natural killer cells as well as hematopoietic progenitor cells. In normal immune responses, CD27 signaling appears to be limited predominantly by the restricted expression of CD70, which is only transiently expressed by cells of the immune system upon activation. Studies performed in CD27-deficient and CD70-transgenic mice have defined a non-redundant role of this receptor-ligand pair in shaping adaptive T-cell responses. Moreover, adjuvant properties of CD70 have been exploited for the design of anti-cancer vaccines. However, continuous CD27-CD70 interactions may cause immune dysregulation and immunopathology in conditions of chronic immune activation such as during persistent virus infection and autoimmune disease. We conclude that optimal tuning of CD27-CD70 interaction is crucial for the regulation of the cellular immune response. We provide a detailed comparison of costimulation through CD27 with its closely related family members 4-1BB (CD137), CD30, herpes virus entry mediator, OX40 (CD134), and glucocorticoid-induced TNFR family-related gene, and we argue that these receptors do not have a unique function per se but that rather the timing, context, and intensity of these costimulatory signals determine the functional consequence of their activity.
Assuntos
Linfócitos B/imunologia , Ligante CD27/imunologia , Células-Tronco Hematopoéticas/imunologia , Células Matadoras Naturais/imunologia , Linfócitos T/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Animais , Linfócitos B/metabolismo , Ligante CD27/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/imunologia , Transdução de Sinais/imunologia , Linfócitos T/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
Chronic infection results in continuous formation and exhaustion of effector CD8 T cells and in failure of memory CD8 T cell development. Expression of CD70 and other molecules that provide costimulation to T cells is maintained during chronic infection. To analyze the impact of constitutive CD70-driven costimulation, we generated transgenic mice expressing CD70 specifically on T cells. We show that CD70 promoted accumulation of CD8 T cells with characteristics strikingly similar to exhausted effector CD8 T cells found during chronic infection. CD70 on T cells provided costimulation that enhanced primary CD8 T cell responses against influenza. In contrast, memory CD8 T cell maintenance and protection against secondary challenge with influenza was impaired. Interestingly, we found no effect on the formation of either effector or memory CD4 T cells. We conclude that constitutive expression of CD70 is sufficient to deregulate the CD8 T cell differentiation pathway of acute infection reminiscent of events in chronic infection.
Assuntos
Ligante CD27/fisiologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Memória Imunológica , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Doença Aguda , Animais , Ligante CD27/biossíntese , Ligante CD27/deficiência , Ligante CD27/genética , Linfócitos T CD8-Positivos/classificação , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Doença Crônica , Homeostase/genética , Homeostase/imunologia , Memória Imunológica/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Ativação Linfocitária/genética , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Coriomeningite Linfocítica/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Subpopulações de Linfócitos T/classificaçãoRESUMO
Glucocorticoid-induced TNF receptor family-related protein (GITR) is expressed on activated and regulatory T cells, but its role on these functionally opposing cell types is not fully understood. Here we describe that transgenic expression of GITR's unique ligand (GITRL) induces a prominent increase of both effector and regulatory CD4(+) T cells, but not CD8(+) T cells. Regulatory T cells from GITRL transgenic mice are phenotypically activated and retain their suppressive capacity. The accumulation of effector and regulatory T cells is not due to enhanced differentiation of naive T cells, but is a direct result of increased proliferation. Functional consequences of increased numbers of both regulatory and effector T cells were tested in an autoimmune model and show that GITR stimulation is protective, as it significantly delays disease induction. These data indicate that GITR regulates the balance between regulatory and effector CD4(+) T cells by enhancing proliferation of both populations in parallel.
Assuntos
Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Receptores de Fator de Crescimento Neural/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Animais , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Células Cultivadas , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Proteína Relacionada a TNFR Induzida por Glucocorticoide , Humanos , Memória Imunológica/imunologia , Interleucina-2/biossíntese , Interleucina-2/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Fator de Crescimento Neural/deficiência , Receptores de Fator de Crescimento Neural/genética , Receptores do Fator de Necrose Tumoral/deficiência , Receptores do Fator de Necrose Tumoral/genéticaRESUMO
Differentiation of naïve CD4(+) T cells to functional effector T-helper (T(H)) cells is driven by both costimulatory molecules and cytokines. Although polarizing cytokines can induce the differentiation into a particular T(H)-subset, certain costimulatory molecules also seem to affect this polarization process. We have previously found that CD70-transgenic (CD70TG) mice develop large numbers of IFN-γ-producing CD4(+) T cells and we therefore questioned whether CD27 triggering provides an instructive signal for T(H)1 differentiation or rather supports T(H) cell formation in general. Although CD70TG mice on a T(H)1-prone C57Bl/6J background develop more T(H)1 cells, we found that this phenotype is lost when CD70TG mice are fully backcrossed on a T(H)2-prone Balb/c background, but is not replaced with more T(H)2 cells. Furthermore, CD70-overexpression is not sufficient to drive T(H)17 cell formation, nor does it affect the generation of FoxP3(+) regulatory T cells. Using an in vitro setting, we found that CD27-triggering does not provide instructive signals for a specific T(H) cell subset, but, depending on the cytokine milieu and genetic background, supports T(H)1 cell formation, while it inhibits the formation of T(H)17 but not T(H)2 cells. Induction of allergic airway inflammation in CD70TG Balb/c mice further illustrates that CD27 plays a supportive role in T(H)1 differentiation in vivo, without modulating the classical T(H)2 response. This supportive role of CD27 in T(H) cell polarization could not be attributed to a specific change of transcription factor expression levels. In summary, this study indicates that CD27 signalling does influence T(H) cell differentiation, but that it is highly dependent on the conditions and genetic background.
Assuntos
Diferenciação Celular/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Animais , Linfócitos B/imunologia , Ligante CD27/imunologia , Homeostase/imunologia , Hipersensibilidade/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Sistema Respiratório/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Fatores de Transcrição/metabolismoRESUMO
Chronic infection and inflammation are strongly associated with the development of atherosclerosis. To investigate whether chronic inflammation in the absence of an infectious cause also predisposes to the development of atherosclerosis, we used a mouse model in which sterile inflammation is driven by enhanced costimulation. Constitutive triggering of CD27 on T cells through overexpression of CD70 on B cells increases the numbers of IFN gamma-producing effector T cells, which reduces the numbers of B cells. However, despite these pro-atherogenic features, we found that CD70-transgenic (CD70TG) mice on an ApoE*3-Leiden background were strongly protected against the induction of atherosclerotic lesions, with a normal increase in serum cholesterol level and the absence of atheroprotective antibodies. We found that circulating monocytes in CD70TG mice were activated and increased in numbers, in particular the pool of inflammatory (Ly6C(+)) monocytes. Importantly, monocytes from CD70TG mice had no defects in phagocytosis nor in TNFalpha production, but they were more prone to apoptosis, which was IFN gamma-dependent. These data indicate that sterile pro-inflammatory conditions can be protective against atherosclerosis development, possibly due to a reduced viability of circulating monocytes. This unexpected outcome provides a new insight into the consequences of costimulatory signals and their impact on innate immunity.