Abstract
BackgroundCD28neg T cells, which display functional characteristic of oligoclonally expanded cytotoxic memory T lymphocytes, are believed to be pathologically relevant in rheumatoid arthritis manifestation. The CD28 co-stimulation blockade by abatacept can prevent the generation of CD28neg T-cell populations in these patients.MethodsSamples were obtained before and after 12 months of abatacept therapy. T-cell phenotype and T-cell receptor diversity were evaluated by flow cytometry and complementarity-determining region-3 spectratyping, respectively, while telomerase reverse-transcriptase gene level was measured by real-time PCR.ResultsAbatacept induces a decrease of the percentage and number of CD4+CD28neg T cells and a reduction of T-cell repertoire restrictions; these features are directly correlated. Thymic output and telomerase activity are not modified by the therapy.ConclusionsAbatacept-induced decrease of peripheral T-cell repertoire restrictions can due to a reduced generation of senescent, chronically stimulated CD4+CD28neg T cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0363-2) contains supplementary material, which is available to authorized users.
Highlights
Several changes of the T-cell compartment have been described in rheumatoid arthritis (RA) patients, which include, in some patients, an increased number of T cells lacking the CD28 costimulatory molecule, which are clonally expanded [1]
Phenotypic characterization of circulating T cells The percentage and number of CD4+CD28neg T cells did not differ between RA patients and healthy controls (HC) before therapy initiation, but the median percentage of these cells was significantly reduced after 12 months of ABA (Table 2)
CD8+CD28neg T cells, which were significantly higher in RA patients at Before abatacept therapy (T0), significantly decreased at after 12 months of abatacept therapy (T12)
Summary
Several changes of the T-cell compartment have been described in rheumatoid arthritis (RA) patients, which include, in some patients, an increased number of T cells lacking the CD28 costimulatory molecule, which are clonally expanded [1]. The emergence of CD28neg T cells has been attributed to repeated antigenic stimulation induced by chronic inflammation or latent infections, especially by cytomegalovirus [2,3] These clonal T lymphocytes, which display functional characteristic of cytotoxic memory T cells and are resistant to apoptosis, are believed to be pathologically relevant in RA development [4], and their increase has been related to worse prognosis and extra-articular manifestations [5]. We studied whether thymic output and apoptosis modifications were involved in these changes For this latter purpose, since telomerase reverse transcriptase (TERT) insufficiency resulting in excessive T-cell apoptosis [11] has been described in RA patients, we evaluated TERT activity before and after therapy with ABA. The CD28 co-stimulation blockade by abatacept can prevent the generation of CD28neg T-cell populations in these patients
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