TSLP Induces TNFα Production by CD1c Myeloid Dendritic Cells and Myeloid DC-Activated T Cells From Rheumatoid Arthritis Patients

F.M. Moret¹, T.R.D.J. Radstake², J.W.J. Bijlsma¹, F.P.J.G. Lafeber¹ and J.A.G. van Roon³, ¹Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ²Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ³Rheumatology & Clinical Immunology/Lab Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: cytokines, dendritic cells and rheumatoid arthritis (RA), T cells

Session Information

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.

Disclosure:

F. M. Moret,
None;

T. R. D. J. Radstake,
None;

J. W. J. Bijlsma,
None;

F. P. J. G. Lafeber,
None;

J. A. G. van Roon,
None.

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