Session Type: Abstract Submissions (ACR)
Background/Purpose: Abatacept is an effective treatment for a subset of rheumatoid arthritis (RA) patients, interfering in the interaction between antigen-presenting cells and T cells preventing T cell activation. Thymic stromal lymphopoietin (TSLP) and the related cytokine IL-7 are both increased in synovial fluid (SF) of RA patients and are shown to contribute to immunopathological mechanisms in RA. Recently, we have shown that TSLP potently activates CD4 T cells via myeloid dendritic cells (mDCs) depending on antigen presentation and co-stimulation. IL-7 directly acts on T cells and strongly induces T cell-dependent activation of antigen-presenting cells. The aim of this study was to investigate the potential of abatacept in inhibiting TSLP-mDC driven naïve and memory T cell activation in the presence of IL-7 in healthy controls (HC) and RA patients.
Methods: Naïve (Tn), central memory (Tcm) and effector memory (Tem) T cell subsets in PB of HC and in PB and SF of RA patients were assessed based on CD27 and CD45RO expression by flow cytometry. CD4 T cell subsets of HC isolated by flow cytometry and T cells from PB and SF of RA patients isolated by MACS were co-cultured with autologous TSLP-stimulated-mDCs with or without abatacept and/or IL-7 and subsequently T cell proliferation was measured.
Results: CD4 T cell subsets from PB of HC and RA patients were comparable and mainly consisted of Tn and Tcm cells (Tn 42 vs. 46%; Tcm 42 vs. 31%; Tem 8 vs. 10%, respectively), whereas SF of RA patients mainly consisted of Tcm and Tem cells (Tn 6%; Tcm 51%; Tem 34%). Activation of these T cell subsets by TSLP-mDCs from PB was completely blocked by abatacept (Tn: 6948 to 114; Tcm: 2347 to 207; Tem: 5718 to 199 cpm, all p<0.05, respectively). IL-7 strongly increased T cell activation and overruled the inhibitory capacity of abatacept (abatacept+IL-7 vs. abatacept, Tn 4836 vs. 114; Tcm 10128 vs. 207; Tem 11605 vs. 199 cpm, all p<0.05, respectively). This IL-7-induced reversal was associated with strong induction of IFNγ and TNFα secretion. Similarly, CD4 T cell proliferation induced by TSLP-stimulated mDCs from SF of RA patients was completely blocked by abatacept and largely reversed in the presence of IL-7.
Conclusion: Our data indicate that the presence of T cell activating cytokines, like IL-7, in joints of RA patients reduce the inhibitory capacity of abatacept on (TSLP-)mDC driven T cell activation. This could possibly explain the unresponsiveness to abatacept in a subset of patients.
F. M. Moret,
T. R. D. J. Radstake,
J. W. J. Bijlsma,
F. P. J. G. Lafeber,
J. A. G. van Roon,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/abatacept-efficacy-is-overruled-by-il-7-in-tslp-primed-myeloid-dendritic-cell-driven-t-cell-activation-from-rheumatoid-arthritis-patients/