Session Type: Abstract Submissions (ACR)
Background/Purpose: Thymic stromal lymphopoietin (TSLP) is well known for its potent activation of myeloid dendritic cells (mDCs) to induce Th2-mediated immune responses. Additionally, TSLP and its receptor play a crucial role in promoting Th17-driven collagen-induced arthritis. Recently, we have shown that increased intra-articular TSLP concentrations in RA patients potently activate TSLPR-expressing mDCs from peripheral blood (PB) and synovial fluid (SF) of RA patients to secrete T cell attractant chemokines and to potently increase Th1, Th17 and Th2 activity. Since TNFα is a crucial pro-inflammatory and tissue-destructive mediator in RA, we assessed the capacity of TSLP to regulate TNFα production by CD1c mDCs and the effects of TNFα blockade in T cell regulation.
Methods: CD1c mDCs, isolated from PB or SF of RA patients, were primed with TSLP for 20 hours without or with anti-TNFα mAb and cytokine production was measured by multiplex immunoassay. Washed TSLP-activated mDCs primed without or with anti-TNFα mAb were added to autologous CD4 T cells in the absence of additional stimuli, cultured for 6 days and subsequently proliferation was measured. Additionally, T-cell cytokine production was measured by ELISA upon restimulation with ionomycin/PMA.
Results: Upon incubation with TSLP, mDCs from PB and SF potently stimulated TNFα production of autologous CD4 T cells as compared to unprimed mDCs (ratio T cell:DC 5:1, PB from 3498 to 9225 pg/ml, p=0.001 and SF from 8951 to 18415 pg/ml, p<0.05). TSLP significantly stimulated the production of TNFα by mDCs from PB and SF (PB from 99 to 378 pg/ml, p<0.05 and SF from 170 to 355 pg/ml, p<0.05). Blockade of TNFα during TSLP-priming of mDCs did not affect T-cell differentiating cytokine production but significantly decreased MIP1α and enhanced TARC production (MIP1a:TARC ratio, TSLP-mDCs versus anti-TNFα-TSLP-mDCs, ratio 40 vs. 3, p<0.05, respectively). Co-culturing TSLP-primed-mDCs that had been treated with anti-TNFα mAb together with T cells did not affect IFNγ and IL-17 production but significantly increased IL-4 production as well as the IFNγ:IL-4 ratio (TSLP-mDCs versus anti-TNFα-TSLP-mDCs, ratio 11 vs. 5, p<0.05, respectively).
Conclusion: TSLP induces TNFα production by CD1c mDCs and mDC-activated CD4 T cells of RA patients. Blockade of TNFα produced by TSLP-primed-mDCs results in the enhancement of Th2 activity by promoting Th2 attracting chemokine production and T cell skewing towards Th2 activity. Considering the inhibitory capacity of Th2 cells in RA, this suggests that TNFα blockade in RA patients contributes to reduced immunopathology by increasing the Th2-inducing potential of TSLP.
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/blockade-of-tnf%ce%b1-produced-by-tslp-primed-cd1c-myeloid-dendritic-cells-skews-t-cell-response-to-th2-activity-in-rheumatoid-arthritis-patients/