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Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity

Abstract

The ability of the human immune system to respond to vaccination declines with age. We identified an age-associated defect in T cell receptor (TCR)-induced extracellular signal–regulated kinase (ERK) phosphorylation in naive CD4+ T cells, whereas other signals, such as ζ chain–associated protein kinase 70 (ZAP70) and phospholipase C-γ1 phosphorylation, were not impaired. The defective ERK signaling was caused by the dual specific phosphatase 6 (DUSP6), whose protein expression increased with age due to a decline in repression by miR-181a. Reconstitution of miR-181a lowered DUSP6 expression in naive CD4+ T cells in elderly individuals. DUSP6 repression using miR-181a or specific siRNA and DUSP6 inhibition by the allosteric inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one improved CD4+ T cell responses, as seen by increased expression of activation markers, improved proliferation and supported preferential T helper type 1 cell differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination.

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Figure 1: Decreased sensitivity of naive CD4+ T cells to respond to antigenic stimulation with age.
Figure 2: Age-associated expression of DUSP6.
Figure 3: Age-associated expression of miR-181a.
Figure 4: miR-181a controls DUSP6 expression.
Figure 5: miR-181a overexpression restores T cell activities in elderly CD4+ T cells.
Figure 6: DUSP6 inhibition augments activation of elderly CD4+ T cells.

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Acknowledgements

J.J.G. was supported by US National Institutes of Health grants U19 AI090019, R01 AG015043 and U19 AI057266, and C.M.W. was supported by US National Institutes of Health grants R01 AR042527, R01 EY011916, R01 AI044142 and PO1 HL058000. Antibody to PTPN22 was a gift from A.C. Chan (Genentech).

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G.L., M.Y., W.-W.L., C.M.W. and J.J.G. designed experiments and analyzed data. G.L., M.Y. and W.-W.L. generated data. M.T. provided BCI and advice in the design of the DUSP6 inhibition experiments. E.K. recruited and clinically phenotyped healthy elderly individuals. G.L. and J.J.G. wrote the manuscript.

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Correspondence to Jörg J Goronzy.

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Li, G., Yu, M., Lee, WW. et al. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat Med 18, 1518–1524 (2012). https://doi.org/10.1038/nm.2963

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