RT Journal Article
SR Electronic
T1 The protein LEM promotes CD8<sup>+</sup> 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.