RESUMO
In chronic lymphocytic leukemia (CLL), signaling through several prosurvival B cell surface receptors activates the PI3K signaling pathway. Idelalisib is a highly selective PI3K (PI3Kδ) isoform-specific inhibitor effective in relapsed/refractory CLL and follicular lymphoma. However, severe autoimmune adverse effects in association with the use of idelalisib in the treatment of CLL, particularly as a first-line therapy, gave indications that idelalisib may preferentially target the suppressive function of regulatory T cells (Tregs). On this background, we examined the effect of idelalisib on the function of human Tregs ex vivo with respect to proliferation, TCR signaling, phenotype, and suppressive function. Our results show that human Tregs are highly susceptible to PI3Kδ inactivation using idelalisib compared with CD4+ and CD8+ effector T cells (Teffs) as evident from effects on anti-CD3/CD28/CD2-induced proliferation (order of susceptibility [IC50]: Treg [.5 µM] > CD4+ Teff [2.0 µM] > CD8+ Teff [6.5 µM]) and acting at the level of AKT and NF-κB phosphorylation. Moreover, idelalisib treatment of Tregs altered their phenotype and reduced their suppressive function against CD4+ and CD8+ Teffs. Phenotyping Tregs from CLL patients treated with idelalisib supported our in vitro findings. Collectively, our data show that human Tregs are more dependent on PI3Kδ-mediated signaling compared with CD4+ and CD8+ Teffs. This Treg-preferential effect could explain why idelalisib produces adverse autoimmune effects by breaking Treg-mediated tolerance. However, balancing effects on Treg sensitivity versus CD8+ Teff insensitivity to idelalisib could still potentially be exploited to enhance inherent antitumor immune responses in patients.
Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Quinazolinonas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Idoso , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Relação Estrutura-Atividade , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
Full T-cell activation critically depends on the engagement of the TCR (T-cell receptor) in conjunction with a second signal by co-stimulatory receptors that boost the immune response. In the present study we have compared signalling patterns induced by the two co-receptors CD2 and CD28 in human peripheral blood T-cells. These co-receptors were previously suggested to be redundant in function. By a combination of multi-parameter phosphoflow cytometry, phosphokinase arrays and Western blot analyses, we demonstrate that CD2 co-stimulation induces phosphorylation of the TCR-proximal signalling complex, whereas CD28 activates distal signalling molecules, including the transcription factors NF-κB (nuclear factor κB), ATF (activating transcription factor)-2, STAT3/5 (signal transducer and activator of transcription 3/5), p53 and c-Jun. These signalling patterns were conserved in both naïve and effector/memory T-cell subsets. We show that free intracellular Ca(2+) and signalling through the PI3K (phosphoinositide 3-kinase)/Akt pathway are required for proper CD28-induced NF-κB activation. The signalling patterns induced by CD2 and CD28 co-stimulation lead to distinct functional immune responses in T-cell proliferation and cytokine production. In conclusion, CD2 and CD28 co-stimulation induces distinct signalling responses and functional outcomes in T-cells.
Assuntos
Antígenos CD2/imunologia , Antígenos CD28/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/fisiologia , Fator 2 Ativador da Transcrição/metabolismo , Cálcio/metabolismo , Humanos , NF-kappa B/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologiaRESUMO
Chronic HIV infection is characterized by chronic immune activation and dysfunctional T cells with elevated intracellular cyclic AMP (cAMP), which inhibits the T cell activation capability. cAMP may be induced by prostaglandin E(2) following lipopolysaccharide (LPS)-induced upregulation of cyclooxygenase type 2 (COX-2) in monocytes due to the elevated LPS levels in patients with chronic HIV infection. This hypothesis was tested using celecoxib, a COX-2 inhibitor, for 12 weeks in HIV-infected patients without antiretroviral treatment in a prospective, open, randomized exploratory trial. Thirty-one patients were randomized in the trial; 27 completed the study, including 13 patients on celecoxib. Celecoxib reduced chronic immune activation in terms of CD38 density on CD8(+) T cells (-24%; P = 0.04), IgA levels (P = 0.04), and a combined score for inflammatory markers (P < 0.05). Celecoxib further reduced the inhibitory surface receptor programmed death 1 (PD-1) on CD8(+) T cells (P = 0.01), including PD-1 on the HIV Gag-specific subset (P = 0.02), enhanced the number of CD3(+) CD4(+) CD25(+) CD127(lo/-) Treg or activated cells (P = 0.02), and improved humoral memory recall responses to a T cell-dependent vaccine (P = 0.04). HIV RNA (P = 0.06) and D dimers (P = 0.07) tended to increase in the controls, whereas interleukin-6 (IL-6) possibly decreased in the treatment arm (P = 0.10). In conclusion, celecoxib downmodulated the immune activation related to clinical progression of chronic HIV infection and improved T cell-dependent functions in vivo.
Assuntos
Vacinas contra a AIDS/imunologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Linfócitos T/imunologia , Vacinas contra a AIDS/administração & dosagem , Adulto , Celecoxib , Doença Crônica , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Progressão da Doença , Regulação para Baixo , Feminino , HIV-1/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of ß-catenin and limiting its nuclear translocation, which is thought to play a gate-keeping role in colorectal cancer. The destruction complex is inhibited by Wnt-Frz and prostaglandin E(2) (PGE(2)) - PI-3 kinase pathways. Recent reports show that PGE(2)-induced phosphorylation of ß-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE(2) on ß-catenin homeostasis. FINDINGS: Treatment of Apc(Min/+) mice that spontaneously develop intestinal adenomas with a PKA antagonist (Rp-8-Br-cAMPS) selectively targeting only the latter pathway reduced tumor load, but not the number of adenomas. Immunohistochemical characterization of intestines from treated and control animals revealed that expression of ß-catenin, ß-catenin nuclear translocation and expression of the ß-catenin target genes c-Myc and COX-2 were significantly down-regulated upon Rp-8-Br-cAMPS treatment. Parallel experiments in a human colon cancer cell line (HCT116) revealed that Rp-8-Br-cAMPS blocked PGE(2)-induced ß-catenin phosphorylation and c-Myc upregulation. CONCLUSION: Based on our findings we suggest that PGE(2) act through PKA to promote ß-catenin nuclear translocation and tumor development in Apc(Min/+) mice in vivo, indicating that the direct regulatory effect of PKA on ß-catenin nuclear translocation is operative in intestinal cancer.
Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Núcleo Celular/metabolismo , Transformação Celular Neoplásica/patologia , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Ciclo-Oxigenase 2/genética , Proteínas Proto-Oncogênicas c-myc/genética , beta Catenina/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/análogos & derivados , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Transporte Ativo do Núcleo Celular , Animais , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo , Células HCT116 , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Tionucleotídeos/farmacologiaRESUMO
The complexity of immunoregulation has focused attention on the CD4+ T "suppressor" regulatory cell (Treg), which helps maintain balance between immunity and tolerance. An immunoregulatory T-cell population that upon activation amplifies cellular immune responses was described in murine models more than 30 years ago; however, no study has yet identified a naturally occurring T "inducer" cell type. Here, we report that the ectoenzyme CD39/NTPDase1 (ecto-nucleoside triphosphate diphosphohydrolase 1) helps to delineate a novel population of human "inducer" CD4+ T cells (Tind) that significantly increases the proliferation and cytokine production of responder T cells in a dose-dependent manner. Furthermore, this unique Tind subset produces a distinct repertoire of cytokines in comparison to the other CD4+ T-cell subsets. We propose that this novel CD4+ T-cell population counterbalances the suppressive activity of suppressor Treg in peripheral blood and serves as a calibrator of immunoregulation.
Assuntos
Antígenos CD/imunologia , Apirase/imunologia , Linfócitos T CD4-Positivos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/citologia , Proliferação de Células , Citocinas/biossíntese , Citocinas/imunologia , Humanos , Subpopulações de Linfócitos T/citologiaRESUMO
Recent studies have indicated that Treg contribute to the HIV type 1 (HIV-1)-related immune pathogenesis. However, it is not clear whether T cells with suppressive properties reside within the HIV-1-specific T-cell population. Here, PBMC from HIV-1-infected individuals were stimulated with a 15-mer Gag peptide pool, and HIV-1-specific T cells were enriched by virtue of their secretion of IL-10 or IFN-gamma using immunomagnetic cell-sorting. Neither the IL-10-secreting cells nor the IFN-gamma-secreting cells expressed the Treg marker FOXP3, yet the IL-10-secreting cells potently suppressed anti-CD3/CD28-induced CD4(+) as well as CD8(+) T-cell proliferative responses. As shown by intracellular cytokine staining, IL-10- and IFN-gamma-producing T cells represent distinct subsets of the HIV-1-specific T cells. Our data collectively suggest that functionally defined HIV-1-specific T-cell subsets harbor potent immunoregulatory properties that may contribute to HIV-1-associated T-cell dysfunction.
Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Interleucina-10/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Proliferação de Células , Citometria de Fluxo , Fatores de Transcrição Forkhead/sangue , Fatores de Transcrição Forkhead/imunologia , Infecções por HIV/sangue , Humanos , Separação Imunomagnética , Interferon gama/sangue , Interferon gama/imunologia , Interleucina-10/sangue , Leucócitos Mononucleares/imunologia , Estatísticas não Paramétricas , Subpopulações de Linfócitos T/citologia , Linfócitos T Reguladores/citologiaRESUMO
Monocytes initiate innate immune responses and interact with T cells to induce antigen-specific immune responses by antigen presentation and secretion of humoral factors. We have previously shown that adaptive regulatory T cells inhibit T-cell effector functions in a cyclooxygenase (COX)-2-prostaglandin E(2) (PGE(2))-dependent manner and that PGE(2) converts resting CD4+CD25- T cells into FOXP3+ T cells with a suppressive phenotype. Here, we demonstrate that stimulation of monocytes with LPS leads to suppression of T-cell immune responses by a COX-2-PGE(2)-dependent mechanism that is reversible with COX-2 inhibitors as well as PGE(2)-neutralizing antibody and cAMP antagonist. Furthermore, we show that LPS-activated monocytes induce FOXP3 expression in resting CD4+CD25- T cells by the same pathway. These results suggest that monocytes are able to efficiently suppress T-cell immune responses in a regulatory manner and elicit an inhibitory immune profile.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Lipopolissacarídeos/farmacologia , Monócitos/imunologia , Linfócitos T/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Comunicação Celular/imunologia , Citocinas/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/deficiência , Ativação Linfocitária/imunologiaRESUMO
Human CD4+CD25+ regulatory T (T(R)) cells express the transcription factor forkhead box p3 (FOXP3) and have potent immunosuppressive properties. While naturally occurring T(R) cells develop in the thymus, adaptive T(R) cells develop in the periphery from naive CD4+ T cells. Adaptive T(R) cells may express cyclooxygenase type 2 (COX-2) and suppress effector T cells by a PGE(2)-dependent mechanism, which is reversible with COX inhibitors. In this study we have characterized the differentiation of naive CD4+ T cells into adaptive T(R) cells in detail during 7 days of continuous antigen stimulation. After 2 days of stimulation of CD4+CD25- T cells, the cells expressed FOXP3 and COX-2 and displayed potent immunosuppressive properties. The suppressive phenotype was present at all observed time-points from Day 2, although suppression was merely present at Day 7. The adaptive T(R) cells expressed cell surface markers consistent with an activated phenotype and secreted high levels of TGF-beta, IL-10, and PGE(2). However, the suppressive phenotype was found exclusively in cells that proliferated upon activation. These data support the notion that activation of naive CD4+ T cells leads to concomitant acquisition of effector and suppressive properties.
Assuntos
Antígenos CD4/análise , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Fatores de Transcrição Forkhead/análise , Subunidade alfa de Receptor de Interleucina-2/análise , Linfócitos T Reguladores/imunologia , Animais , Antígenos de Bactérias/farmacologia , Doadores de Sangue , Linfócitos T CD4-Positivos/efeitos dos fármacos , Diferenciação Celular , Divisão Celular , Técnicas de Cocultura , Enterotoxinas/farmacologia , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Humanos , Terapia de Imunossupressão , Camundongos , Camundongos Endogâmicos BALB C , Baço/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacosRESUMO
Human CD4(+)CD25(hi)FOXP3(+) regulatory T cells maintain immunologic tolerance and prevent autoimmune and inflammatory immune responses. Regulatory T cells undergo a similar activation cycle as conventional CD4(+) T cells upon antigen stimulation. Here, we demonstrate that T cell receptors and costimulation are required to activate the regulatory T cell suppressive function. Regulatory T cells suppressed the T cell receptor signaling in effector T cells in a time-dependent manner that corresponded with inhibition of cytokine production and proliferation. Modulation of the activation level and thereby the suppressive capacity of regulatory T cells imposed distinct T cell receptor signaling signatures and hyporesponsiveness in suppressed and proliferating effector T cells and established a threshold for effector T cell proliferation. The immune suppression of effector T cells was completely reversible upon removal of regulatory T cells. However, the strength of prior immune suppression by regulatory T cells and corresponding T cell receptor signaling in effector T cells determined the susceptibility to suppression upon later reexposure to regulatory T cells. These findings demonstrate how the strength of the regulatory T cell suppressive function determines intracellular signaling, immune responsiveness, and the later susceptibility of effector T cells to immune suppression and contribute to unveiling the complex interactions between regulatory T cells and effector T cells.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Tolerância Imunológica/imunologia , Terapia de Imunossupressão , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Células Cultivadas , Citocinas/metabolismo , Humanos , Ativação Linfocitária , Transdução de SinaisRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is highly infiltrated by CD4+T cells that express RORγt and IL-17 (TH17). Compelling evidence from the tumor microenvironment suggest that regulatory T cells (Treg) contribute to TH17 mediated inflammation. Concurrently, PDAC patients have elevated levels of pro-inflammatory cytokines that may lead to TH17 associated functional plasticity in Treg. In this study, we investigated the phenotype and functional properties of Treg in patients with PDAC. We report that PDAC patients have elevated frequency of FOXP3+Treg, which exclusively occurred within the FOXP3+RORγt+Treg compartment. The FOXP3+RORγt+Treg retained FOXP3+Treg markers and represented an activated subset. The expression of RORγt in Treg may indicate a phenotypic switch toward TH17 cells. However, the FOXP3+RORγt+Treg produced both TH17 and TH2 associated pro-inflammatory cytokines, which corresponded with elevated TH17 and TH2 immune responses in PDAC patients. Both the FOXP3+Treg and FOXP3+RORγt+Treg from PDAC patients strongly suppressed T cell immune responses, but they had impaired anti-inflammatory properties. We conclude that FOXP3+RORγt+Treg have a dual phenotype with combined pro-inflammatory and immunosuppressive activity, which may be involved in the pathogenesis of PDAC.
RESUMO
The immune system faces the difficult task of discerning between foreign, potentially pathogen-derived antigens and self-antigens. Several mechanisms, including deletion of self-reactive T cells in the thymus, have been shown to contribute to the acceptance of self-antigens and the reciprocal reactivity to foreign antigens. Over the last decade it has become increasingly clear that CD4(+)CD25(+) T(Reg) cells are crucial for maintenance of T cell tolerance to self-antigens in the periphery, and to avoid development of autoimmune disorders. Recently, evidence has also emerged that demonstrates that CD4(+)CD25(+) T(Reg) cells can also suppress T cell responses to foreign pathogens, including viruses such as HIV. In this article we review the current knowledge and potential role of CD4(+)CD25(+) T(Reg) cells in HIV infection.
Assuntos
Linfócitos T CD4-Positivos/fisiologia , Infecções por HIV/imunologia , Receptores de Interleucina-2/fisiologia , Linfócitos T CD4-Positivos/virologia , HumanosAssuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Infecções por HIV/tratamento farmacológico , Indometacina/uso terapêutico , Lactonas/uso terapêutico , Linfócitos T/imunologia , Adulto , Terapia Antirretroviral de Alta Atividade , Divisão Celular , Feminino , Infecções por HIV/imunologia , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Sulfonas , Carga ViralRESUMO
OBJECTIVE: Naturally occurring regulatory T (T(R)) cells suppress autoreactive T cells whereas adaptive T(R) cells, induced in the periphery, play an important role in chronic viral diseases and cancer. Several studies indicate that cyclooxygenase (COX) inhibitors prevent cancer development of colon adenomas and delay disease progression in patients with colorectal cancer (CRC). We have shown that adaptive T(R) cells express COX-2 and produce PGE(2) that suppress effector T cells in a manner that is reversed by COX-inhibitors. METHODS AND RESULTS: Here we demonstrate that CRC patients have elevated levels of PGE(2) in peripheral blood, and CRC tissue samples and draining lymph nodes display increased numbers of FOXP3+ T(R) cells. Depletion of T(R) cells from PBMC enhanced anti-tumor T-cell responses to peptides from carcinoembryonic antigen. Furthermore, the COX inhibitor indomethacin and the PKA type I antagonist Rp-8-Br-cAMPS significantly improved the anti-tumor immune activity. CONCLUSION: We suggest that adaptive T(R) cells contribute to an immunosuppressive microenvironment in CRC and inhibit effector T cells by a COX-2-PGE(2)-dependent mechanism and thereby facilitate tumor growth. Therapeutic strategies targeting T(R) cells and the PGE(2)-cAMP pathway may be interesting to pursue to enhance anti-tumor immune activity in CRC patients.
Assuntos
Neoplasias Colorretais/imunologia , Ciclo-Oxigenase 2/metabolismo , Imunoterapia/métodos , Linfócitos T Reguladores/citologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Neoplasias Colorretais/patologia , Dinoprostona/metabolismo , Feminino , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Linfócitos T Reguladores/imunologiaRESUMO
cAMP negatively regulates T cell immune responses by activation of type I protein kinase A (PKA), which in turn phosphorylates and activates C-terminal Src kinase (Csk) in T cell lipid rafts. Using yeast two-hybrid screening, far-Western blot, immunoprecipitation and immunofluorescense analyses, and small interfering RNA-mediated knockdown, we identified Ezrin as the A-kinase anchoring protein that targets PKA type I to lipid rafts. Furthermore, Ezrin brings PKA in proximity to its downstream substrate Csk in lipid rafts by forming a multiprotein complex consisting of PKA/Ezrin/Ezrin-binding protein 50, Csk, and Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomains. The complex is initially present in immunological synapses when T cells contact APCs and subsequently exits to the distal pole. Introduction of an anchoring disruptor peptide (Ht31) into T cells competes with Ezrin binding to PKA and thereby releases the cAMP/PKA type I-mediated inhibition of T cell proliferation. Finally, small interfering RNA-mediated knockdown of Ezrin abrogates cAMP regulation of IL-2. We propose that Ezrin is essential in the assembly of the cAMP-mediated regulatory pathway that modulates T cell immune responses.
Assuntos
Proteínas de Ancoragem à Quinase A/fisiologia , Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo , AMP Cíclico/farmacologia , Proteínas do Citoesqueleto/fisiologia , Imunossupressores/farmacologia , Microdomínios da Membrana/fisiologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Proteínas de Ancoragem à Quinase A/química , Proteínas de Ancoragem à Quinase A/metabolismo , Actinas/metabolismo , Células Cultivadas , Clonagem Molecular , Proteína Quinase Tipo I Dependente de AMP Cíclico/antagonistas & inibidores , Proteína Quinase Tipo I Dependente de AMP Cíclico/genética , Proteínas do Citoesqueleto/antagonistas & inibidores , Proteínas do Citoesqueleto/genética , Citoesqueleto/imunologia , Citoesqueleto/metabolismo , Humanos , Células Jurkat , Microdomínios da Membrana/metabolismo , Mapeamento de Peptídeos , Fosfoproteínas/fisiologia , Ligação Proteica , RNA Interferente Pequeno/farmacologia , Complexo Receptor-CD3 de Antígeno de Linfócitos T/metabolismo , Transdução de Sinais/imunologia , Trocadores de Sódio-Hidrogênio/fisiologia , Linfócitos T/enzimologiaRESUMO
CD4+CD25+ regulatory T (T(R)) cells suppress effector T cells by partly unknown mechanisms. In this study, we describe a population of human suppressive CD4+CD25+ adaptive T(R) (T(R)(adapt)) cells induced in vitro that express cyclooxygenase 2 (COX-2) and the transcription factor FOXP3. T(R)(adapt) cells produce PGE(2) and suppress effector T cell responses in a manner that is reversed by COX inhibitors and PGE(2) receptor-specific antagonists. In resting CD4+CD25- T cells, treatment with PGE(2) induced FOXP3 expression. Thus, autocrine and paracrine effects of PGE(2) produced by COX-2-positive T(R)(adapt) cells may be responsible for both the FOXP3+ phenotype and the mechanism used by these cells to suppress effector T cells.
Assuntos
Ciclo-Oxigenase 2/biossíntese , Dinoprostona/fisiologia , Fatores de Transcrição Forkhead/biossíntese , Receptores de Interleucina-2/biossíntese , Subpopulações de Linfócitos T/enzimologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/enzimologia , Linfócitos T Reguladores/imunologia , Comunicação Celular/imunologia , Células Cultivadas , AMP Cíclico/biossíntese , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/antagonistas & inibidores , Dinoprostona/biossíntese , Dinoprostona/metabolismo , Enterotoxinas/farmacologia , Fatores de Transcrição Forkhead/fisiologia , Humanos , Imunidade Inata , Imunossupressores/antagonistas & inibidores , Imunossupressores/farmacologia , Ativação Linfocitária/imunologia , Antagonistas de Prostaglandina/fisiologia , Receptores de Prostaglandina E/antagonistas & inibidores , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/microbiologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/microbiologiaRESUMO
Regulatory T (T(R)) cells maintain tolerance to self-antigens and control immune responses to alloantigens after organ transplantation. Here, we show that CD4(+) CD25(+) human T(R) cells suppress virus-specific T-cell responses. Depletion of T(R) cells from peripheral blood mononuclear cells enhances T-cell responses to cytomegalovirus and human immunodeficiency virus antigens. We propose that chronic viral infections lead to induction of suppressive T(R) cells that inhibit the antiviral immune response.
Assuntos
Antígenos Virais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Citomegalovirus/imunologia , HIV/imunologia , Receptores de Interleucina-2/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Citometria de Fluxo , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Ativação Linfocitária , Superantígenos/imunologiaRESUMO
The adaptive immune response of human CD8 T cells to invading pathogens involves the differentiation of naive cells into memory and effector cells. However, the lineage relationship between memory and effector cells and the differentiation of CD8 T cells into distinct subsets of effector cell subpopulations are subjects of considerable debate. CD7 identifies three populations of CD8 T cells: CD7 high (CD7(high)), low (CD7(low)), and negative (CD7(neg)) that translate into subsets with distinct functional properties. The CD7(high) subset contains naive and memory cells and the CD7(low) and CD7(neg) subsets contain effector cells. The effector cells can functionally be divided into cytokine-secreting effector CD8 T cells and lytic effector CD8 T cells. These data provide a model of human CD8 T cell differentiation in which specialized distinct subpopulations can be identified by expression of CD7.
Assuntos
Antígenos CD7/análise , Linfócitos T CD8-Positivos/imunologia , Subpopulações de Linfócitos T/imunologia , Antígenos CD7/biossíntese , Biomarcadores/análise , Linfócitos T CD8-Positivos/química , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Divisão Celular/imunologia , Células Cultivadas , Citocinas/biossíntese , Citotoxicidade Imunológica , Regulação para Baixo/imunologia , Epitopos de Linfócito T/análise , Humanos , Memória Imunológica , Imunofenotipagem , Interfase/imunologia , Contagem de Linfócitos , Subpopulações de Linfócitos T/química , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Forkhead/winged helix (FOX) transcription factors are essential for control of the cell cycle and metabolism. Here, we show that spleens from Mf2-/- (FOXD2-/-) mice have reduced mRNA (50%) and protein (35%) levels of the RIalpha subunit of the cAMP-dependent protein kinase. In T cells from Mf2-/- mice, reduced levels of RIalpha translates functionally into approximately 2-fold less sensitivity to cAMP-mediated inhibition of proliferation triggered through the T cell receptor-CD3 complex. In Jurkat T cells, FOXD2 overexpression increased the endogenous levels of RIalpha through induction of the RIalpha1b promoter. FOXD2 overexpression also increased the sensitivity of the promoter to cAMP. Finally, co-expression experiments demonstrated that protein kinase Balpha/Akt1 work together with FOXD2 to induce the RIalpha1b promoter (10-fold) and increase endogenous RIalpha protein levels further. Taken together, our data indicate that FOXD2 is a physiological regulator of the RIalpha1b promoter in vivo working synergistically with protein kinase B to induce cAMP-dependent protein kinase RIalpha expression, which increases cAMP sensitivity and sets the threshold for cAMP-mediated negative modulation of T cell activation.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas de Ligação a DNA/metabolismo , Linfócitos T/metabolismo , Transativadores/metabolismo , Linfócitos B/metabolismo , AMP Cíclico/metabolismo , AMP Cíclico/farmacologia , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico , Fatores de Transcrição Forkhead , Humanos , Células Jurkat , Ativação Linfocitária/efeitos dos fármacosRESUMO
The antiviral response of CD8 T cells involves the differentiation of naive T cells into distinct types of effector and memory cells, which may be distinguished by the level of CD7 expression. We have investigated CD8 T cells in adults and children infected with HIV-1 to determine the disease relevance of cell subsets defined by CD7. CD8 T cells from patients infected with HIV-1 displayed profound down-modulation of CD7 expression as compared with healthy subjects, with expansion of both CD7(low) and CD7(negative) effector subsets. Loss of CD7(high) cells correlated directly with HIV-1 load and was particularly pronounced in patients with rapid disease progression. CD8 T cells specific for HIV-1, as well as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were predominantly found in the CD7(low) effector cell subset. Furthermore, recovery of CD4 counts on antiretroviral therapy was associated with reversion of the skewed CD7 profile in CD8 T cells. Thus, effector CD8 T-cell subsets distinguished by lowered CD7 expression expand in a manner that correlates with the magnitude of HIV-1, EBV, and CMV antigenic challenge and contract in response to successful antiretroviral treatment. The results are discussed in relation to the dual roles of CD7 as a receptor of both costimulation and cell death.