Research Article

The protein LEM promotes CD8+ T cell immunity through effects on mitochondrial respiration

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Science  29 May 2015:
Vol. 348, Issue 6238, pp. 995-1001
DOI: 10.1126/science.aaa7516

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LEM gets T cells the energy they need

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. 976


Protective 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.

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