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

Previous studies on classical CD4 T cell subsets described reduced proliferation, lower IL-2 secretion, and accumulation of metabolic defects, along with higher production of pro-inflammatory mediators.

“For example, previous studies performed on classical CD4 T cell subsets described reduced proliferation, lower secretion of interleukin-2 (IL-2) cytokine (7, 8), and accumulation of metabolic defects (9), along with higher production of pro-inflammatory mediators (10).”

Increased DUSP6 expression in naive CD4+ T cells is due to an age-related decline in miR-181a expression.

“In this regard, the increased expression of DUSP6 in naive CD4 + T cells described above was due to the age-related decline in miR-181a expression (88).”

Increased DUSP6 expression in naive CD4+ human T cells causes activation of a smaller fraction of Th cells, especially with low-affinity stimuli.

“A subsequent report from the same laboratory described the increased expression of DUSP6 in naive CD4 + human T cells, which resulted in activation of a lower fraction of Th cells, particularly in response to low-affinity stimuli (88).”

Lowering DUSP6 by raising miR-181a or using the inhibitor BCI improves old naive CD4+ T cell responsiveness.

“the reduction of DUSP6 levels by increasing miR-181a expression or repressing activity with the allosteric inhibitor BCI improved the responsiveness of old naive CD4 + T cells (88).”

Naïve T cells from old people show altered TCR signaling and TCR-induced ERK phosphorylation, resulting in blunted activation.

“Altered TCR signaling and TCR-induced ERK phosphorylation, resulting in blunted activation, have been reported in CD4+ and CD8+ naïve T cells from old people [81, 82].”

In naïve CD4+ T cells, desensitization of the TCR cascade is associated with increased activity of DUSP6, a negative regulator of the ERK pathway.

“In naïve CD4+ T cells, the desensitization of the TCR cascade was even associated with increased activity of dual specific phosphatase 6 [DUSP6], a negative regulator of the ERK pathway [81].”

Reconstitution of miR-181a lowered DUSP6 expression in naive CD4+ T cells in elderly individuals.

“Reconstitution of miR-181a lowered DUSP6 expression in naive CD4+ T cells in elderly individuals [81].”

An age-associated defect in TCR-induced ERK phosphorylation in naive CD4+ T cells was identified.

“Furthermore, Li et al. [81] identified an age-associated defect in T-cell receptor (TCR)-induced ERK phosphorylation in naive CD4+ T cells.”

The defective ERK signaling was caused by DUSP6, whose protein expression increased with age due to a decline in repression by miR-181a.

“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.”