RESUMEN
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.
Asunto(s)
Linfocitos T CD8-positivos , Simportadores , Animales , Ratones , Linfocitos T CD8-positivos/metabolismo , Ácido Láctico/metabolismo , Transporte Biológico , Simportadores/genética , Simportadores/metabolismoRESUMEN
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.
Asunto(s)
Antígeno B7-H1/genética , Linaje de la Célula/inmunología , Interferón gamma/genética , Receptor de Muerte Celular Programada 1/genética , Linfocitos T/inmunología , Adenosina Trifosfato/antagonistas & inhibidores , Adenosina Trifosfato/biosíntesis , Animales , Anticuerpos Monoclonales/farmacología , Antimetabolitos Antineoplásicos/farmacología , Antígeno B7-H1/inmunología , Linaje de la Célula/efectos de los fármacos , Linaje de la Célula/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Diazooxonorleucina/farmacología , Compuestos Epoxi/farmacología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Glucólisis/efectos de los fármacos , Interferón gamma/antagonistas & inhibidores , Interferón gamma/inmunología , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Subunidad gamma Común de Receptores de Interleucina/genética , Subunidad gamma Común de Receptores de Interleucina/inmunología , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Oligomicinas/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/trasplante , Trasplante HomólogoRESUMEN
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.