Scientists have identified a protein that may represent a target for the design of drugs capable of re-energizing the immune system in elderly people. It’s well recognized that as we age our immune systems become weaker, and less effective at beating chronic infections and, critically, responding to potentially life-saving vaccination. Current approaches to improving vaccine responses are focused primarily on antigen presentation by increasing antigen dose. However, Stanford University School of Medicine investigators have now found that blocking the dual-specific phosphatase DUSP6 in naive CD4+ T cells in elderly people allows the cells to respond in a much more sprightly manner to presented antigens.
DUSP6 is expressed in naive CD4+ T cells, and plays a key role in T-cell receptor (TCR)-induced extracellular signal-regulated kinase (ERK) phosphorylation and activation, which is a key player in the feedback loops involved in early T-cell responses. “ERK activity is a pivotal regulator of TCR threshold calibration, as it controls positive feedback loops in the TCR-induced activation cascade; reduced ERK activity impairs signal strength and activation of individual T cells,” explain Jörg J. Goronzy, M.D., and colleagues.
The team’s studies on T cells from relative young (20–35 years of age) and much older (70–85 years) individuals showed that naive CD4+ T cells in elderly people required much higher levels of antigen stimulation to trigger TCR activation. Moreover, this decline in sensitivity was linked with an age-related increase in DUSP6 levels specifically in the naive CD4+ T cells (but not memory T cells), caused by a parallel age-related decline in expression of miR-181a, a microRNA that normally acts to inhibit DUSP6. “The higher levels of DUSP6 raise the threshold for productive T-cell activation by dampening the initial ERK signal after TCR stimulation,” the team states. In fact, the researchers found that DUSP6 levels increased linearly with increasing age.
A causal relationship between increased DUSP6 and miR-181a was supported by the finding that changing DUSP6 protein levels weren’t reflected at the transcript level: DUSP6 transcript numbers in total CD4+ T cells taken from either young or elderly individuals were roughly the same. Rather, it appears to be inhibition by miR-181a that impacts the level of DUSP6 protein translation. In fact, the inverse relationship between naive CD4+ levels of DUSP6 and miR-181a held true up till about age 55, after which, the investigators suggest, miR-181a levels are probably too low to influence DUSP6 production.
This causal link between miR-181a expression, DUSP6 levels, and immune response was further supported through studies in which CD4+ T cells from elderly individuals were transfected with an miR-181a precursor. The transfected cells exhibited much lower levels of DUSP6 protein than nontransfected CD4+ T cells, and also, notably, a significantly improved ERK response.
To see whether DUSP6 blockade could directly impact T-cell activation, the researchers then transfected CD4+ T cells from elderly individuals with one of two DUSP6-targeting siRNAs, and stimulated the cells with suboptimal concentrations of antibodies to CD3 and CD28, two molecules that play a key role in the signaling cascade triggered when a peptide MHC ligand binds to the TCR. The results showed that both the DUSP6-silencing siRNAs led to increased production of the T-cell activation marker CD69, and increased proliferative responses and IL-2 production.
Similar effects were seen when peripheral blood mononuclear cells from elderly individuals were treated using a pharmacological inhibitor of DUSP6 known as BCI ((E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one), and the cells were subsequently stimulated with CD3 and CD28 antibodies. Again, the naive T cells demonstrated elevated expression of the activation markers CD69 and CD25, and increased proliferative responses and production of IL-2.
“Our studies suggest that, in addition to vaccine preparation, vaccination strategies in the elderly may have to include direct targeting of the T cells by lowering the TCR activation threshold and modifying early TCR signaling,” the researchers claim. “Inhibition of DUSP6 could be a key intervention to strengthen and broaden naive CD4+ T cell responses in the elderly.”
Dr. Goronzy et al report their research and findings in Nature Medicine in a paper titled “Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity.”
