Metabolic Regulation of Differentiation

Science Signaling  15 Nov 2011:
Vol. 4, Issue 199, pp. ec317
DOI: 10.1126/scisignal.4199ec317

Upon activation, CD4+ T cells differentiate into effector T cells (Teffs) or regulatory T cells (Tregs), which promote or suppress immune responses, respectively. Whereas Teffs rely on glycolytic metabolism for their differentiation, Tregs use lipid oxidation. Noting that tumor cells also rely on glycolytic metabolism, Michalek et al. investigated whether Teffs and tumor cells might share similar transcriptional control of their metabolism. Estrogen-related receptor-α (ERRα) is an orphan nuclear receptor that controls metabolism and is associated with tumor cell growth. The authors found that the abundance of ERRα protein increased in CD4+ T cells stimulated through the T cell receptor (TCR) and the co-receptor CD28 compared with that in unstimulated cells. Although young ERRα–/– mice had numbers and subsets of T cells similar to those of wild-type mice, older ERRα–/– mice had reduced numbers of Teffs. Gene expression analysis showed that treatment of CD4+ T cells with XCT790, an inverse agonist of ERRα that promotes its degradation, resulted in decreased expression of genes that encode enzymes required for glycolytic metabolism. Loss of ERRα or its inhibition inhibited both the stimulation and proliferation of CD4+ T cells. Addition of a mixture of fatty acids, but not pyruvate, increased the mitochondrial function and proliferation of XCT790-treated CD4+ T cells. During the TCR stimulation of naïve CD4+ T cells in the presence of XCT790, the addition of fatty acids facilitated their generation into Tregs but not Teffs. Finally, in a peptide-induced mouse model of multiple sclerosis, loss or inhibition of ERRα decreased the numbers of Teffs, but not those of Tregs, which resulted in less severe disease compared with that observed in wild-type mice. Thus, the authors suggest that targeting ERRα may result in modulation of immune responses by selectively inhibiting Teff generation.

R. D. Michalek, V. A. Gerriets, A. G. Nichols, M. Inoue, D. Kazmin, C.-Y. Chang, M. A. Dwyer, E. R. Nelson, K. N. Pollizzi, O. Ilkayeva, V. Giguere, W. J. Zuercher, J. D. Powell, M. L. Shinohara, D. P. McDonnell, J. C. Rathmell, Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation. Proc. Natl. Acad. Sci. U.S.A. 108, 18348–18353 (2011). [Abstract] [Full]