Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 127, Issue 10, Pages 3609-3623Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI90895
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Funding
- NIH [DK080949, OD008469, AI095277, P41GM103533, AI072117, T32DK007202, F32AG039127]
- UCSD Digestive Diseases Research Development Center [DK80506]
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During an immune response, CD8(+) T lymphocytes can undergo asymmetric division, giving rise to daughter cells that exhibit distinct tendencies to adopt terminal effector and memory cell fates. Here we show that pre-effector and pre-memory cells resulting from the first CD8(+) T cell division in vivo exhibited low and high rates of endogenous proteasome activity, respectively. Pharmacologic reduction of proteasome activity in CD8(+) T cells early during differentiation resulted in acquisition of terminal effector cell characteristics, whereas enhancement of proteasome activity conferred attributes of memory lymphocytes. Transcriptomic and proteomic analyses revealed that modulating proteasome activity in CD8(+) T cells affected cellular metabolism. These metabolic changes were mediated, in part, through differential expression of Myc, a transcription factor that controls glycolysis and metabolic reprogramming. Taken together, these results demonstrate that proteasome activity is an important regulator of CD8(+) T cell fate and raise the possibility that increasing proteasome activity may be a useful therapeutic strategy to enhance the generation of memory lymphocytes.
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