2Protective CD8 + T cell-mediated immunity requires a massive expansion in cell number and the development of long-lived memory cells. Using forward genetics in mice, we identified an orphan protein named Lymphocyte Expansion Molecule (LEM) that promoted antigen-dependent CD8 + T cell proliferation, effector function and memory cell generation in response to infection with lymphocytic choriomeningitis virus. Generation of LEM-deficient mice confirmed these results.Through interaction with CR6 interacting factor (CRIF1), LEM controlled the levels of oxidative phosphorylation (OXPHOS) complexes and respiration resulting in the production of pro-proliferative mitochondrial Reactive Oxygen Species (mROS).LEM provides a link between immune activation and the expansion of protective CD8 + T cells driven by OXPHOS and represents a pathway for the restoration of long-term protective immunity based on metabolically modified CTL. 3Cytotoxic CD8 + T cells (CTL) are a central arm of the immune system responsible for protection from intracellular viruses and cancer because they kill infected or transformed cells (1). Since chronic virus infection (2) and cancer (3) are wide spread diseases it is clear that CTL-immunity often fails. A major reason for this failure is because high viral (4, 5) or tumor (6-8) load results in either deletion or functional inactivation (known as immune exhaustion) of CTL. The result is failure in both short-term CTL immunity and immunological memory because memory CD8 T cell development is blocked (9). Impaired expansion is an important cause of deletion and immune exhaustion and results in the failure to produce sufficient numbers of protective CTL and memory cells (5). Retro mutant mice have increased immunity to chronic viral infectionInfection of wild-type C57BL/6 mice with the clone 13 variant of lymphocytic choriomeningitis virus (LCMV C13) is an established model for human chronic viral infection resulting in a massive viral load that causes both deletion and immune exhaustion of CTL and a block in memory CD8 T cell development (10).We examined the CTL response to LCMV C13 infection after germ-line mutagenesis to identify mutants with enhanced immunity. To this end, 430 third-generation (G3) ethyl-N-nitrosourea (ENU)-induced germ-line mutants were produced in a C57BL/6J background (11). G3 mice were infected with LCMV C13 and after 8 days the level of LCMV-specific CD8 T cells measured in the spleen by staining with a tetramer for the np396 LCMV peptide and flow-cytometry (12). Three independent germ-line transmissible modifications, which resulted in increased levels of LCMV-specific 4 CD8 T cells were isolated, of which one (a semi-dominant) was bred to homozygosity (Fig. S1a). We named this strain Retro.Homozygous Retro mutant mice showed a 10-fold increase in CD8 T cells specific for LCMV np396 peptide compared to wild-type (WT) and a smaller but significant increase in the number of CTL specific for the gp33-LCMV peptide ( Fig. 1 a, b).Compared to WT mice, a smaller percentage of Retr...
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