RESUMO
Energy metabolism is essential for T cell function. However, how persistent antigenic stimulation affects T cell metabolism is unknown. Here, we report that long-term in vivo antigenic exposure induced a specific deficit in numerous metabolic enzymes. Accordingly, T cells exhibited low basal glycolytic flux and limited respiratory capacity. Strikingly, blockade of inhibitory receptor PD-1 stimulated the production of IFNγ in chronic T cells, but failed to shift their metabolism towards aerobic glycolysis, as observed in effector T cells. Instead, chronic T cells appeared to rely on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to produce ATP for IFNγ synthesis. Check-point blockade, however, increased mitochondrial production of superoxide and reduced viability and effector function. Thus, in the absence of a glycolytic switch, PD-1-mediated inhibition appears essential for limiting oxidative metabolism linked to effector function in chronic T cells, thereby promoting survival and functional fitness.
Assuntos
Antígeno B7-H1/genética , Linhagem da Célula/imunologia , Interferon gama/genética , Receptor de Morte Celular Programada 1/genética , Linfócitos T/imunologia , Trifosfato de Adenosina/antagonistas & inibidores , Trifosfato de Adenosina/biossíntese , Animais , Anticorpos Monoclonais/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Antígeno B7-H1/imunologia , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Diazo-Oxo-Norleucina/farmacologia , Compostos de Epóxi/farmacologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Glicólise/efeitos dos fármacos , Interferon gama/antagonistas & inibidores , Interferon gama/imunologia , Subunidade gama Comum de Receptores de Interleucina/deficiência , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/imunologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Oligomicinas/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/transplante , Transplante HomólogoRESUMO
T-cell metabolism is central to the shaping of a successful immune response. However, there are pathological situations where T cells are rendered dysfunctional and incapable of eliminating infected or transformed cells. Here, we review the current knowledge on T-cell metabolism and how persistent antigenic stimulation, in the form of cancer and chronic viral infection, modifies both metabolic and functional pathways in T cells.
Assuntos
Reprogramação Celular/imunologia , Metabolismo Energético/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adaptação Biológica/genética , Adaptação Biológica/imunologia , Animais , Antígenos/imunologia , Reprogramação Celular/genética , Metabolismo Energético/genética , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Memória Imunológica , Ativação Linfocitária/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/citologia , Viroses/imunologia , Viroses/metabolismoRESUMO
The protein S100A4 is best known for its significant role in promoting motility and invasive capacity of cancer cells. Since S100A4 expression has been reported also in T cells, we analyzed its potential role in T cell motility and inflammation. Using S100a4(+/Gfp) mice, we show here that S100A4 is exclusively expressed by memory T cells of CD4(+) or CD8(+) subpopulations, predominantly of the effector memory T cell subtype. However, the protein was not required for in vitro memory T cell migration toward gradients of the inflammatory chemokine CXCL10. Moreover, T cell memory response was normal in S100A4-deficient mice and lack of S100a4 gene expression did not induce any defect in promoting the development of protective immunity or inflammatory reactions leading to autoimmunity. Taken together, our results demonstrate that S100A4 activity is dispensable for T cell motility/migration and inflammatory potential.
RESUMO
CD3-negative NK cells are granular lymphocytes capable of producing inflammatory cytokines and killing malignant, infected, or stressed cells. We have recently observed a new role for NK cells in the control of the proliferation of CD4 T cells under persistent antigenic stimulation. Monoclonal anti-male CD4 T cells transferred into Rag2-/- male recipients did not expand or were rapidly eliminated. Remarkably, T cells transferred into NK cell-deficient Rag2-/- Il-2Rgammac-/- male hosts expanded extensively and mediated tissue lesions usually observed in chronic graft-versus-host disease (GVHD). T cell failure to proliferate and to induce chronic GVHD was the result of NK cell activity, because depletion of the recipient's NK1.1+ cells by Ab treatment induced T cell expansion and chronic GVHD. T cells under chronic Ag stimulation upregulated ligands of the activating receptor NKG2D, and regulatory activity of NK cells was inhibited by the injection of Abs directed to NKG2D. On the contrary, blocking NKG2A inhibitory receptors did not increase NK cell regulatory activity. Finally, we show that NK regulation of T cell expansion did not involve perforin-mediated lytic activity of NK cells, but depended on T cell surface expression of a functional Fas molecule. These results highlight the potential role played by NK cells in controlling the Ag-specific CD4+ T cells responsible for chronic GVHD.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Transferência Adotiva , Animais , Proliferação de Células , Separação Celular , Feminino , Citometria de Fluxo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Mice made unresponsive by repeated injection of staphylococcal enterotoxin B (SEB) contained SEB-specific CD25(+)CD4(+)TCRBV8(+) T cells that were able to transfer their state of unresponsiveness to primary-stimulated T cells. About one-half of these cells stably up-regulated the expression of CD152. We undertook the present study to determine whether CD152(high) cells seen in this system were T regulatory cells responsible for suppression or whether they represented SEB-activated CD4(+) T effector cells. Our results show that, among SEB-specific TCRBV8(+) T cells isolated from unresponsive mice, all CD152(high)CD25(+)CD4(+) T cells expressed Foxp3, the NF required for differentiation and function of natural T regulatory cells. Moreover, suppression by CD25(+)CD4(+)TCRBV8(+) T cells was fully inhibited by anti-CD152 Abs. Following stimulation by soluble CD152-Ig, dendritic cells (DC) isolated from unresponsive mice strongly increased the expression and the function of indoleamine-2,3-dioxygenase (IDO), the enzyme responsible for the catabolism of tryptophan. This capacity to activate IDO was independent of IFN-gamma production by DC because CD152-Ig stimulation of DC isolated from SEB-treated IFN-gamma-deficient animals activated IDO expression and function. Finally, adding 1-methyl-tryptophan, an inhibitor of tryptophan catabolism, increased substantially the capacity of DC from unresponsive animals to stimulate primary T cell response toward SEB. Thus, we conclude that IFN-gamma-independent CD152-mediated activation of tryptophan catabolism by Foxp3(+)CD25(+) T regulatory cells provides DC with immune regulatory activity in mice unresponsive to SEB.
Assuntos
Antígenos CD/biossíntese , Antígenos de Diferenciação/biossíntese , Células Dendríticas/imunologia , Enterotoxinas/imunologia , Tolerância Imunológica/fisiologia , Linfócitos T Reguladores/imunologia , Triptofano/metabolismo , Animais , Western Blotting , Antígeno CTLA-4 , Cromatografia Líquida de Alta Pressão , Ativação Enzimática , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/biossíntese , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interferon gama/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/metabolismoRESUMO
The repeated injection of low doses of bacterial superantigens (SAg) is known to induce specific T cell unresponsiveness. We show in this study that the spleen of BALB/c mice receiving chronically, staphylococcal enterotoxin B (SEB) contains SEB-specific CD4(+) TCRBV8(+) T cells exerting an immune regulatory function on SEB-specific primary T cell responses. Suppression affects IL-2 and IFN-gamma secretion as well as proliferation of T cells. However, the suppressor cells differ from the natural CD4(+) T regulatory cells, described recently in human and mouse, because they do not express cell surface CD25. They are CD152 (CTLA-4)-negative and their regulatory activity is not associated with expression of the NF Foxp3. By contrast, after repeated SEB injection, CD4(+)CD25(+) splenocytes were heterogenous and contained both effector as well as regulatory cells. In vivo, CD4(+)CD25(-) T regulatory cells prevented SEB-induced death independently of CD4(+)CD25(+) T cells. Nevertheless, SEB-induced tolerance could not be achieved in thymectomized CD25(+) cell-depleted mice because repeated injection of SEB did not avert lethal toxic shock in these animals. Collectively, these data demonstrate that, whereas CD4(+)CD25(+) T regulatory cells are required for the induction of SAg-induced tolerance, CD4(+)CD25(-) T cells exert their regulatory activity at the maintenance stage of SAg-specific unresponsiveness.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Anergia Clonal/imunologia , Enterotoxinas/administração & dosagem , Receptores de Interleucina-2/biossíntese , Superantígenos/administração & dosagem , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD , Antígenos de Diferenciação/biossíntese , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/microbiologia , Antígeno CTLA-4 , Movimento Celular/imunologia , Separação Celular , Relação Dose-Resposta Imunológica , Regulação para Baixo/imunologia , Esquema de Medicação , Enterotoxinas/imunologia , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/imunologia , Feminino , Injeções Intraperitoneais , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos BALB C , Baço/citologia , Baço/imunologia , Staphylococcus aureus/imunologia , Superantígenos/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/microbiologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/microbiologia , Timo/citologia , Timo/imunologiaRESUMO
BACKGROUND: Dendritic cells (DC) at the immature state express low levels of major histocompatibility complex and costimulatory molecules and are poor stimulators of primary T-cell response in vitro. Injection of immature bone marrow-derived DC, however, was shown to prime in vivo alloreactive CD4 T lymphocytes toward type 2 cytokine-producing cells in the absence of CD8 T-cell activation. METHODS: We undertook the present study to determine whether Th2-immunization by immature DC could lead to allograft rejection. We first analyzed, in the major histocompatibility complex class II antigen-disparate B6-anti-bm12 combination, the capacity of immature DC to regulate the activity of alloreactive CD4 T cells. We then determined, in this model of weak antigenicity, whether injection of bm12 DC in B6 recipients before transplantation could modify the survival of vascularized bm12 cardiac allografts. RESULTS: We confirmed that in vitro immature DC are poor stimulators of T-cell alloresponse. However, when given in vivo, immature bm12 DC primed anti-bm12 T cells for the production of interleukin (IL)-4. Moreover, they induced the acute rejection of bm12 cardiac allograft. The process of rejection was dependent on IL-4 because immunization of IL-4-deficient mice did not trigger rejection. CONCLUSIONS: Allogeneic immature DC generated with granulocyte-macrophage colony-stimulating factor are potent stimulators of primary alloreactive response in vivo and prime for transplant rejection. Our results indicate that strategies based on immature DC for the induction of transplantation tolerance should be considered with caution.