Expression of the monocarboxylate transporter MCT1 is required for virus-specific mouse CD8 <sup>+</sup> T cell memory development
Stefania d'Aria, Céline Maquet, Shuang Li, Suveera Dhup, Anouk Lepez, Arnaud Köhler, Vincent F. Van Hée, Rajesh K. Dadhich, Marine Frenière, Fabienne Andris, Ivan Nemazanyy, Pierre Sonveaux, Bénédicte Machiels, Laurent Gillet, Michel Y. Braun
Abstract
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.