RT Journal Article SR Electronic T1 The protein LEM promotes CD8+ T cell immunity through effects on mitochondrial respiration JF Science JO Science FD American Association for the Advancement of Science SP 995 OP 1001 DO 10.1126/science.aaa7516 VO 348 IS 6238 A1 Okoye, Isobel A1 Wang, Lihui A1 Pallmer, Katharina A1 Richter, Kirsten A1 Ichimura, Takahuru A1 Haas, Robert A1 Crouse, Josh A1 Choi, Onjee A1 Heathcote, Dean A1 Lovo, Elena A1 Mauro, Claudio A1 Abdi, Reza A1 Oxenius, Annette A1 Rutschmann, Sophie A1 Ashton-Rickardt, Philip G. YR 2015 UL http://science.sciencemag.org/content/348/6238/995.abstract AB During an infection, T cells proliferate extensively to build a sufficient army to defeat the invading pathogen. Carefully regulated changes in metabolism let T cells do this, but the specific nature of these changes is not fully understood. Using forward genetics in mice to screen for genes that regulate T cell immunity, Okoye et al. identified a mutation in the gene that encodes a protein they named lymphocyte expansion molecule (LEM) (see the Perspective by O'Sullivan and Pearce). LEM enhanced T cell immunity, including both proliferation and memory cell generation, in response to chronic viral infection. LEM facilitated these changes through effects on mitochondrial respiration.Science, this issue p. 995; see also p. 976Protective 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 cytotoxic CD8+ T cells.