Session Title: Cytokines, Mediators, and Gene Regulation
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. Fibroblasts from rheumatoid arthritis (RA) patients produce TSLP upon TLR and TNFα stimulation. 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 T cell activation. In addition, TSLP and its receptor play a crucial role in promoting Th17-driven collagen-induced arthritis. 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 CD4 T cells in RA patients as compared to healthy controls (HC).
Methods: CD1c mDCs, isolated from PB as well as SF of RA patients (n=6), were stimulated with TSLP for 20 hours and TNFα production was measured by multiplex immunoassay. Washed TSLP-activated CD1c mDCs from PB (n=13) and SF (n=5) of RA patients and from PB of HC (n=5) 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 TNFα production was measured by ELISA upon restimulation with ionomycin/PMA.
Results: TSLP significantly stimulated the production of TNFα by mDCs from PB and SF (PB from 99 to 378 pg/ml, p<0.03 and SF from 170 to 355 pg/ml, p<0.03). Upon incubation with TSLP, TSLPR-expressing mDCs from PB potently stimulated proliferation of autologous CD4 T cells as compared to unstimulated mDCs (ratio T cell:DC 5:1, from 1503 to 16036 cpm, p<0.01). TSLP-mDCs from SF had a strongly increased capacity to activate CD4 T cells (ratio T cell:DC 5:1, from 26395 to 57387 cpm, p<0.05). Enhanced proliferation was associated with increased production of TNFα (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). TNFα production by TSLP-mDC activated T cells from PB of RA patients was higher as compared to HC (RA from 3498 to 9225 pg/ml and HC from 3522 to 5686 pg/ml), although this was not statistically significant.
Conclusion: TSLP potently induces TNFα production by CD1c mDCs and mDC-activated CD4 T cells from RA patients. Considering the fact that TNFα can induce TSLP secretion by synovial fibroblasts this suggests a novel positive feedback loop of TNFα and TSLP that contributes to immunopathology of RA.
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/tslp-induces-tnf%ce%b1-production-by-cd1c-myeloid-dendritic-cells-and-myeloid-dc-activated-t-cells-from-rheumatoid-arthritis-patients/