Editors' ChoiceImmunology

Making Immunological Memories

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Science Signaling  07 Jul 2009:
Vol. 2, Issue 78, pp. ec225
DOI: 10.1126/scisignal.278ec225

Exposure of CD8 T cells to their cognate antigen elicits a proliferative response that leads to generation of a population of effector T (TE) cells ready to fight the offending pathogen. During this proliferative phase, T cells rely on glycolytic metabolism, a metabolic predilection promoted by cytokines, such as interleukin-2 (IL-2). Although most of the TE cells die during the contraction phase that follows resolution of the infection, a minority differentiate into long-lived memory T (TM) cells, which provide an immunological memory that facilitates subsequent responses to the pathogen (see Prlic and Bevan). Two groups now present evidence that pathways implicated in cellular metabolism also play a critical role in TM cell generation. Pearce et al. found that mouse CD8 T cells lacking tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6, an adaptor protein that acts as a negative regulator of T cell activation) proliferated normally in response to antigen, but their generation of TM cells (and mouse response to reinfection) was impaired. Microarray analyses indicated that, 10 days post infection, the TRAF6-deficient T cells had defects in the expression of genes involved in fatty acid metabolism and other metabolic pathways. Unlike wild-type CD8 T cells, the TRAF6-deficient cells failed to respond to withdrawal of IL-2 with increased fatty acid oxidation (FAO), and they showed decreased activation of AMP-activated kinase (AMPK). Treatment with the antidiabetic drug metformin, which activates AMPK, enabled FAO oxidation after IL-2 withdrawal in TRAF6-deficient cells. Furthermore, metformin promoted the in vivo generation of both wild-type and TRAF6-deficient TM cells, as well as the response to reinfection, as did inhibition of mTOR (mammalian target of rapamycin) signaling with rapamycin, which also promotes FAO. It was intriguing that metformin treatment enhanced the efficacy of an anticancer vaccine.

In the second study, Araki et al. were surprised to find that rapamycin (used as an immunosuppressive drug) decreased the contraction of mouse CD8 T cells following the response to lymphocytic choriomeningitis virus (LCMV) infection. Moreover, CD8 TM cells generated in the presence of rapamycin had a phenotype associated with superior function compared to that of TM cells generated in its absence. Rapamycin administration during the proliferation phase (days 1 to 8) increased the number of memory cell precursors (the cells that survive and give rise to long-lived TM cells), whereas treatment during the contraction phase (days 8 to 35) affected the phenotype. Similar effects were seen in the mouse response to viruslike particles and in Rhesus macaques. Experiments in which different elements of the mTOR pathway were knocked down in CD8 T cells, which were then transferred into naïve mice, indicated that the response was intrinsic to CD8 T cells and implicated not only mTOR and the mTOR complex 1 component raptor, but also the downstream effectors S6K1 and eIF4E. Thus, both papers implicate cellular metabolic pathways in the generation of CD8 TM cells, and raise the possibility of manipulating such pathways to enhance immunological memory.

K. Araki, A. P. Turner, V. O. Shaffer, S. Gangappa, S. A. Keller, M. F. Bachmann, C. P. Larsen, R. Ahmed, mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009). [PubMed]

E. L. Pearce, M. C. Walsh, P. J. Cejas, G. M. Harms, H. Shen, L.-S. Wang, R. G. Jones, Y. Choi, Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009). [PubMed]

M. Prlic, M. J. Bevan, A metabolic switch to memory. Nature 460, 41–42 (2009). [PubMed]

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