Background/Purpose: T cells abnormality is an essential part in the pathogenesis of rheumatoid arthritis (RA), which includes a signature of premature immune aging, and restricted proliferative potential of naïve T cells. Shelterin complex is critical for maintaining Telomeres, which are important regulators of aging. We hypothesized that shelterin deficiency may play a key role in the senescence of RA T cells.

Methods: Naïve CD4 T cells were isolated from 29 Newly-onset treatment-naive RA patients and 38 gender-and age- matched healthy controls (HC) . The expression of six shelterin subunits was assessed in naïve and activated CD4 T cells. Critical DNA damage responses and the role of TRF2 in cell apoptosis were tested as well.

Results: The mRNA levels of subunits TRF1, TRF2, Rap1 and TPP1, except POT1 and TIN2, were significantly lower in RA naïve CD4 T cells compare with those from HC. TCR stimulation significantly up-regulated all subunit expression in both group in a time-dependent manner, but the level of healthy controls remained higher than RA patients. Additionally, the deficiency of shelterin subunits were independent of disease activity (measured by DAS28), disease duration or treatment. Consistently, DNA lesions related to apoptosis triggers, including ATM, CHK2, H2AX histone, p53, p21 and GADD45, were up-regulated in RA naïve CD4 T cells compared with HC. Finally, by TRF2-silencing, we showed loss of telomere protection by shelterin ultimately resulted in ATM-p53-dependent DNA damage response in naïve CD4 T cells, which was correlated with caspase-3 activation.

Conclusion: Shelterin deficiency of naïve CD4 T cells in RA patient may be involed in the perturbed T cell homeostasis, and restore T cell competence may be a potential therapeutic target.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-role-of-shelterin-deficiency-in-the-senescence-in-t-cells-of-rheumatoid-arthritis/