BackgroundRheumatoid arthritis is a chronic inflammatory disease with a strong MHC class II component and where many patients develop characteristic autoantibodies towards the noncoding amino acid citrulline. Such anti-citrullinated protein antibodies (ACPA) have recently been put forward as an independent predictive factor for treatment response by co-stimulation blockade by CTLA4-Ig (abatacept). We have performed a mechanism of action study to dissect T cell functionality in RA patients with long-standing disease undergoing abatacept treatment and the influence of ACPA status.ResultsPeripheral blood samples were collected from RA patients as they started CTLA4-Ig treatment and 3 and 6 months later. A general decrease of regulatory T cell subsets was observed in the cohort. Additionally within the ACPA-positive group significant down-regulation of all key T cell effector subsets including Th1, Th2, and Th17 was observed by analyzing cytokines by intracellular flow cytometry and in cell culture supernatants.RA synovial fluid samples were cultured in vitro in the presence or absence of CTLA4-Ig (abatacept). T cell cytokine production was diminished, but without increasing the functional capacity of CD4+CD25hi regulatory T cells as previously demonstrated in the context of TNF-blockade and anti-IL6R therapy.ConclusionsOur immunological study of T cell functionality in RA patients, both ACPA-positive and ACPA-negative, starting biological therapy with the co-stimulation blockade abatacept (CTLA4-Ig) supports the recently published registry study implicating ACPA seropositivity as an independent predictive factor to treatment response as we observed the most striking effect on T cell subset modulation in ACPA-positive patients. These data further support the notion of RA as a disease with several sub-entities, where the ACPA-positive fraction represents a classical HLA-associated autoimmune disorder while ACPA-negative patients may have other driving forces apart from classical adaptive immune responses.
Regulatory T cells (Tregs) are important for maintaining immune homeostasis, but many studies suggest that Tregs are functionally impaired in autoimmune and chronic inflammatory disorders. In addition, effector T cells may vary in sensitivity toward Treg suppression. Herein, we have studied the interplay between T effectors and Tregs in the rheumatic joint. Synovial Tregs demonstrated a high degree of FOXP3 demethylation and displayed only marginal IL-17 and virtually no IFN-c production following in vitro stimulation, altogether indicating suppressive capacity. Still, the frequency of FOXP3 expression could not predict the degree of suppression. Instead, the inflammatory milieu in the joint, i.e. proliferative capacity of effector T cells and in situ levels of pro-inflammatory cytokines influenced Treg function. Indeed, blocking IL-6 or TNF increased the suppression by Tregs in co-cultures. Additionally, approximately 30% of the synovial FOXP3 1 T cells were Ki67 1 and hence actively dividing, but proliferation did not overlap with cytokine production, suggesting that these cells represent functional Tregs having met their cognate antigen and expanded in an attempt to alleviate joint inflammation. Overall, our data argue against a general functional deficit in joint-derived Tregs and instead emphasize the importance of the inflammatory milieu to set the threshold for immune regulation.
The presence of the PTPN22 risk allele (1858T) is associated with several autoimmune diseases including rheumatoid arthritis (RA). Despite a number of studies exploring the function of PTPN22 in T cells, the exact impact of the PTPN22 risk allele on T-cell function in humans is still unclear. In this study, using RNA sequencing, we show that, upon TCR-activation, naïve human CD4 T cells homozygous for the PTPN22 risk allele overexpress a set of genes including CFLAR and 4-1BB, which are important for cytotoxic T-cell differentiation. Moreover, the protein expression of the T-box transcription factor Eomesodermin (EOMES) was increased in T cells from healthy donors homozygous for the PTPN22 risk allele and correlated with a decreased number of naïve CD4 T cells. There was no difference in the frequency of other CD4 T-cell subsets (Th1, Th17, Tfh, Treg). Finally, an accumulation of EOMES CD4 T cells was observed in synovial fluid of RA patients with a more pronounced production of Perforin-1 in PTPN22 risk allele carriers. Altogether, we propose a novel mechanism of action of PTPN22 risk allele through the generation of cytotoxic CD4 T cells and identify EOMES CD4 T cells as a relevant T-cell subset in RA pathogenesis.
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