Role of the Monocarboxylate transporter 1 (MCT1) in T lymphocytes

Upon activation, T cells shift towards a metabolic program characterized by increased glucose metabolism in order to sustain proliferation and effector function. Surprisingly, while resting T lymphocytes degrade glucose aerobically to CO2, proliferating T cells metabolize glucose almostentirely to lactate in the presence of oxygen through aerobic glycolysis (the Warburg effect). This metabolic switch comprises the upregulation of glycolytic enzymes and glucose transporters to the cell membrane, leading to an increase of glycolytic flux and the concomitant production of lactate. Despite many decades of research, we still do not fully understand the mechanisms that make proliferating T cells choose glycolysis rather than oxidation of glucose to produce energy. Since activated T lymphocytes depend on a glycolytic metabolism, they must release lactate, which inthese cells is facilitated by the proton-linked monocarboxylate transporter MCT1. The transporter is part of a protein family of 14 members among which MCT1–4 facilitate the passive transmembrane transport of monocarboxylates such as lactate, pyruvate and ketone bodies. The observation that pharmacological MCT1 inhibition has shown anti-proliferative effect on T cells suggests that lactate transport is essential to T cell expansion triggered after antigen recognition. The aim of our research is to investigate the importance of MCT1-dependent regulation in T cellmetabolism. Following TCR stimulation, MCT1 was expressed early in T cells unlike MCT4 whose significant expression was detected at later time point. To investigate the role played by MCT1 in the early steps of T cell activation, we generated a transgenic mouse model where conditional deletion of the MCT1 gene was achieved specifically in T cells. Phenotype and T cell distribution in thymus and peripheral organs were normal in MCT1fl/fl CD4Cre mice. However, lack of MCT1 expression decreased the proliferative capacity of in vitro activated CD4+ or CD8+ T cells without altering their viability. We observed that the IL-2 production was also affected by the lack of MCT1 expression, in line with decreased proliferative ability. Moreover, in vivo, T cell expansion that followed antigenic stimulation as well as T cell-mediated immune response to infection were deficient in MCT1fl/flCD4Cre mice. Our data indicate that this situation resulted from a cellular energy shortage caused by reduced glycolytic activity soon after activation. Moreover, energy crisis was amplified by the necessity to use ATP-consuming mechanisms for excluding H+ protons from the cytosol of activated MCT1-deficient T cells. Thus, in T cells, early MCT1 expression after activation ensures an energy saving mechanism for regulating cytoplasm acidification. Our observations also indicate that a high glycolytic flux is required in dividing T cells to maintain pH homeostasis.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)info:eu-repo/semantics/nonPublishe

Long-term antigen exposure deeply modifies metabolic requirements for T cell function

Energy metabolism is essential for T cell function. However, how persistent antigenic stimulation affects T cell metabolism is unknown. Here, using a model of T cell transfer in mice, we report that long-term 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 chronically stimulated T cells, but failed to shift their metabolism towards aerobic glycolysis, as observed in effector T cells. Instead, chronically stimulated T cells appeared to rely on oxidative phosphorylation (OXPHOS) to produce ATP. PD-1 inhibition, however, increased mitochondrial production of superoxide and reduced viability and effector function. Thus, in the absence of a glycolytic switch, PD-1 inhibition appears essential for limiting oxidative metabolism linked to effector function in chronically stimulated T cells, thereby promoting survival and functional fitness

Expression of the monocarboxylate transporter MCT1 is required for virus-specific mouse CD8+ T cell memory development.

peer reviewedLactate-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

Expression of the monocarboxylate transporter MCT1 is required for virus-specific CD8+ T cell memory development

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, 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 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