Background The T-cell compartment of patients with rheumatoid arthritis (RA) is characterized by profound changes, including an acceleration of immune-senescence, reduced diversity of the T-cell repertoire, and expansion of clonal populations. These changes are reflected by the expansion of the CD28 peripheral blood T-cell subpopulations, as consequence of repeated CD28 engagement induced by chronic inflammation. These populations have been reported to have a reduced telomerase activity. Abatacept (CTLA4-Ig; ABA) can prevent the engagement of CD28 and T-cell activation, avoiding CD28 down-modulation and limiting the expansion of CD28- T cells in RA.
Objectives To evaluate the effect of ABA therapy on T-cell repertoire diversity and senescence in patients with RA.
Methods In 44 RA patients treated with ABA, peripheral blood T cells were evaluated by flow-cytometry at baseline (T0) and after 12 months (T12). Healthy donors (HD) of comparable sex and age were evaluated. In 17 patients, the composition and diversity of T-cell receptor (TR) repertoire was assessed by spectratyping on mRNA extracted from peripheral blood mononuclear cells (PBMC). Average perturbation within CDR3 region of TR beta chain was calculated by measuring the Hamming distance between the target sample and a control CDR3 distribution profile, obtained from HD (theoretical nonperturbed repertoire). Telomerase reverse transcriptase (TERT) expression was assessed by real-time PCR on mRNA extracted from PBMC of 11 patients stimulated with anti-CD3 and expressed, using DDCt method, as normalization rate (NR).
Results At T0, CD4+CD28- T cells did not differ between RA patients and HD. At T12, after ABA therapy, the percentage of circulating CD4+CD28- T cells decreased from 4.5% (IQR: 1.0-25.0) to 1.8% (0.2-12.2) of total CD4+ T cells (p:0.016), and their absolute number from 32 cells/microliter (8-152) to 18 (7-121) (p:0.048). The reduction of CD4+CD28- cells correlated with decrease of disease activity (measured by DAS28-CRP; r:0.43; p:0.045). No variation was seen after therapy in the proportion of recent thymic emigrant T cells (RTE; CD45RA+CD31+CD4+ T cells). At T0, RA patients had a higher TRBV average perturbation than HD (17.0% (13.9-25.8) vs.11.6% (10.0-14.1); p<0.001). TERT expression levels in RA patients did not significantly differ from HD, but was correlated with the average perturbation of TRBV repertoire (r:0.778; p<0.001). At T12, the perturbation of TRBV in RA decreased from 17.0% (13.9-25.8) to 16.6% (11.5-20.5) (p:0.049), with a correlation with CD4+CD28- T cell decrease (r:0.584; p:0.017), but not with the variation of RTE T cell percentage. Similarly, TERT expression did not significantly change during treatment.
Conclusions The observed enlargement of TRBV repertoire diversity and the decreased number of CD4+CD28- cell number after ABA treatment are indicative of a renewal of T-cell compartment that may be explained by the block in the peripheral differentiation of CD4+ memory T cells after antigenic presentation and not by a thymic immune reconstitution.
Acknowledgements We acknowledge Bristol-Myers-Squibb Italia for the support to our study
Disclosure of Interest None Declared
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