RESUMO
Lactate-proton symporter monocarboxylate transporter 1 (MCT1) facilitates lactic acid export from T cells. Here, we report that MCT1 is mandatory for the development of virus-specific CD8+ T cell memory. MCT1-deficient T cells were exposed to acute pneumovirus (pneumonia virus of mice, PVM) or persistent γ-herpesvirus (Murid herpesvirus 4, MuHV-4) infection. MCT1 was required for the expansion of virus-specific CD8+ T cells and the control of virus replication in the acute phase of infection. This situation prevented the subsequent development of virus-specific T cell memory, a necessary step in containing virus reactivation during γ-herpesvirus latency. Instead, persistent active infection drove virus-specific CD8+ T cells toward functional exhaustion, a phenotype typically seen in chronic viral infections. Mechanistically, MCT1 deficiency sequentially impaired lactic acid efflux from activated CD8+ T cells, caused an intracellular acidification inhibiting glycolysis, disrupted nucleotide synthesis in the upstream pentose phosphate pathway, and halted cell proliferation which, ultimately, promoted functional CD8+ T cell exhaustion instead of memory development. Taken together, our data demonstrate that MCT1 expression is mandatory for inducing T cell memory and controlling viral infection by CD8+ T cells.
Assuntos
Linfócitos T CD8-Positivos , Simportadores , Animais , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Ácido Láctico/metabolismo , Transporte Biológico , Simportadores/genética , Simportadores/metabolismoRESUMO
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.
