Elderly humans mount weaker immune responses after infection or vaccination than do younger humans. In Nature Medicine, Goronzy and colleagues identify age-related defects in TCR signaling capacity that lessens the ability to recruit naive CD4+ T cells into immune responses. The lower TCR sensitivity in T cells from elderly people (>70 years of age) is due to higher expression of the dual-specific phosphatase DUSP6, which regulates activation of the kinase Erk and leads to less phosphorylation of Erk after TCR stimulation. This scenario increases the antigenic threshold needed to activate naive T cells. DUSP6 expression is regulated by the microRNA miR-181a. T cells from older humans have lower miR-181a expression than do those from young adults. The responsiveness of naive T cells can be restored by lowering DUSP6 expression or inhibiting its activity with the pharmacological inhibitor BCI. These findings suggest a means of boosting adaptive immunity in the elderly by targeting DUSP6.

Nat. Med. 18, 1518–1524 (2012)