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Fréderique Moret

Thursday 8 May 2014

TSLP-driven activation of CD1c myeloid dendritic cells and T cell activity in rheumatoid arthritis

Promotor: Prof. dr F.P.J.G. Lafeber & prof.dr J.W.J. Bijlsma
Defence: 8 May 2014

Rheumatoid arthritis (RA) is characterized by joint inflammations that is dependent on CD4 T-cells producing Th1 and Th17 cytokines. Activation and differentiation of CD4 T-cells to become Th1 or Th17 cells is regulated by dendritic cells. CD1c (BDCA1) myeloid dendritic cells (mDCs) have a strong capacity to activate CD4 T-cells. The aim of this thesis was to investigate the inflammatory potential of thymic stromal lymphopoietin (TSLP) to activate natural occurring CD1c mDCs and subsequently the regulation of CD4 T-cell responses in RA as well as the capacity of T-cell-targeting therapy (abatacept) to influence TSLP-driven immunopathology in RA.
Compared with CD1c mDCs from peripheral blood (PB), increased numbers of intra-articular CD1c mDCs expressed an activated phenotype and secreted a unique set of T-cell-attracting chemokines and spontaneously induced Th1, Th17, and Th2 cell activity. TSLP levels were significantly increased in synovial fluid (SF) of RA versus osteoarthritis patients. TSLP selectively stimulated production of T-cell-attracting chemokines as well as TNFα by CD1c mDCs. TSLP-primed mDCs from PB and SF potently stimulated proliferation of autologous CD4 T-cells compared with unstimulated mDCs. Enhanced proliferation was associated with increased Th1, Th17, and Th2 cell activity.
TNFα produced by TSLP-stimulated mDCs inhibited Th2 responses by favouring Th1-attracting chemokine production and preventing T-cells to secrete Th2 cytokines. Considering the immunoregulatory capacity of Th2 cells in RA this suggests that TNFα might contribute to TSLP-induced immunopathology in RA.
Activation of PB-derived naïve and memory T-cells by (TSLP-primed) mDCs was completely blocked by the anti-rheumatic drug abatacept. IL-7 strongly increased T-cell activation and overruled the inhibitory capacity of abatacept. Similarly, CD4 T-cell proliferation induced by TSLP-primed mDCs from SF of RA patients, mainly consisting of memory T-cells, was strongly blocked by abatacept and vigorously overruled by IL-7. This indicates that the presence of T-cell-activating cytokines, like IL-7, in RA joints reduce the inhibitory capacity of abatacept on mDC-driven T-cell activation that might explain lack of response to abatacept therapy.
In contrast to PB-derived T-cells, an evident hypo-responsiveness of SF-derived CD4 T-cells upon (TSLP-primed) mDC activation was observed and we investigated the involvement of inhibitory PD-1/PD-L1 interactions. Synovial T-cell hypo-responsiveness upon (TSLP-primed) mDC stimulation in RA joints was partially dependent on PD-1/PD-L1 interactions as PD-1 and PD-L1 were highly expressed on synovial T-cells and mDCs, respectively, and PD-1 blockade during memory T-cell and (TSLP-primed) mDC cocultures from RA patients significantly enhanced but not fully recovered T-cell proliferation. The potential of IL-7 to overrule this hypo-responsiveness suggests that such proinflammatory cytokines in RA joints strongly contribute to memory T-cell activation. Finally, we described that levels of the naturally occurring soluble IL-7Rα (sIL-7Rα) were strongly increased in SF of RA patients compared with osteoarthritis patients and correlated with markers of inflammation. Increased sIL-7Rα might be associated with an increased IL-7-driven immune activation.
This thesis demonstrate an important role for in vivo activated CD1c mDCs to drive T-cell activation in RA and that prevention of TSLP- and IL-7-driven mDC/T-cell activation seem to have therapeutic potential.