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Reduced activity of the double-strand break repair protein MRE11A in patients with rheumatoid arthritis (RA) promotes T-cell ageing and destructive inflammation in synovial tissue, according to a new study by Yinyin Li and colleagues. “MRE11A protein concentrations decline with progressive age in healthy T cells,” explains Cornelia Weyand, corresponding author of the study. “This phenotype is aggravated and premature in RA,” she continues.

Previous studies showed that RA T cells not only have accelerated shortening of telomeres, but also accumulate defects in the protein machinery controlling DNA surveillance and repair. Whether DNA alterations contribute to premature immune ageing and influence the proarthritogenic functions of T cells was not clear, however.

Overexpression of MRE11A in RA T cells prevented cellular ageing and telomere damage

The researchers screened RA CD4+ T cells for DNA repair components involved in protection and maintenance of telomeres, and found that expression of MRE11A in memory and naive T-cell compartments of patients with RA was consistently lower than in those of healthy individuals. In agreement with these results, pharmacological and genetic inhibition of MRE11A in healthy T cells induced an ageing phenotype by upregulating the cell-cycle regulators cyclin-dependent kinase inhibitor 1 and cyclin-dependent kinase inhibitor 2A. In addition, overexpression of MRE11A in RA T cells prevented cellular ageing and telomere damage.

To investigate the role of MRE11A in vivo, Li and colleagues transferred healthy and RA human peripheral blood mononuclear cells (PBMCs) to mice engrafted with human synovial tissue. Pharmacological inhibition of MRE11A increased the tissue invasiveness and proinflammatory functions of RA PBMC-derived T cells. Accordingly, overexpression of MRE11A in RA PBMCs prior to adoptive transfer prevented the arthritogenic effector functions of T cells in the synovial grafts.

These findings provide a mechanistic link between T-cell ageing and proinflammatory cell behaviour. “Understanding on a cellular and molecular level how the immune system ages offers great potential not only for rheumatology and RA, but also for the emerging field of immune health,” points out Weyand. Her group now plans to recover MRE11A expression in patients' T cells to prevent immune ageing and tissue inflammation.