Thymic Stromal Lymphopoietin, a Novel Proinflammatory Mediator in Rheumatoid Arthritis That Potently Activates CD1c+ Myeloid Dendritic Cells to Attract and Stimulate T Cells

Abstract

Objective. To determine the levels of thymic stromal lymphopoietin (TSLP) and the numbers of TSLP receptor (TSLPR)-expressing CD1c؉ (blood dendritic cell antigen 1-positive) myeloid dendritic cells (MDCs) in the joints as compared with the peripheral blood (PB) of patients with rheumatoid arthritis (RA), as well as to determine the capacity of TSLP to induce MDCdependent T cell activation.Methods. TSLP levels were measured in synovial fluid (SF) samples from patients with RA and those with osteoarthritis (OA). MDC numbers in PB and SF samples from RA patients and TSLPR expression on these cells were assessed by fluorescence-activated cell sorter analysis. PB and SF MDCs from RA patients were stimulated with TSLP, and cytokine production was measured by multiplex immunoassay. TSLP-primed MDCs were cocultured with autologous CD4؉ T cells in the absence of additional stimuli, and subsequently, cell proliferation and cytokine production were measured.Results. TSLP levels were significantly increased in SF samples from RA versus OA patients. The numbers of TSLPR-expressing MDCs in the SF of RA patients were significantly increased as compared to those in the PB, and SF MDCs displayed increased levels of TSLPR. TSLP selectively stimulated the production of thymus and activation-regulated chemokine and macrophage inflammatory protein 1␣ by CD1c؉ MDCs. TSLP-primed MDCs from PB and SF potently stimulated the proliferation of autologous CD4؉ T cells as compared to unstimulated MDCs. Enhanced proliferation was associated with increased production of interferon-␥, interleukin-17 (IL-17), and IL-4.Conclusion. These data support an inflammatory mechanism by which increased intraarticular TSLP in RA potently activates TSLPR-expressing CD1c؉ MDCs in the joints to secrete chemokines, causing chemotaxis and subsequent activation of CD4؉ T cells. In addition to the demonstrated inflammatory potential of TSLP in experimental arthritis, this suggests that TSLP and TSLPR-expressing MDCs could both play a pivotal role in the immunopathology of RA.

Targeting CD1c-expressing classical dendritic cells to prevent thymus and activation-regulated chemokine (TARC)-mediated T-cell chemotaxis in rheumatoid arthritis

“…Furthermore, these RA SF cDCs are primed to produce TARC as they make it ex vivo without any stimulation (20). TSLP, which is increased in RA SF, was shown to activate cDCs from PB, and TSLP-stimulated PB DCs mimic functional and phenotypic features of intra-articular cDCs, including TARC production (19). In the current study we demonstrate that TARC is increased in SF of RA patients and that MCs from SF are primed to produce TARC.…”

“…These observations suggest that TARC mediates the migration of pro-inflammatory CCR4-expressing T cells into the joint in RA. Furthermore, it was previously shown that thymic stromal lymphopoietin (TSLP), a strong TARC inducer on cDCs, is increased in the RA SF (19) and that cDCs from the RA SF produce TARC ex vivo (20). The aim of this study was to evaluate TARC levels in SF of RA patients, study the role of cDCs in TARC production in RA joints, and investigate the role of TARC in the attraction of T cells in RA.…”

Potential involvement of IL-9 and Th9 cells in the pathogenesis of rheumatoid arthritis

“…TSLP has been demonstrated to belong to the innate branch of immunity and to drive, also independently of canonical cytokines, the development of Th9 cells. In relation to this, TSLP levels have been found to be significantly increased in SF of RA patients and capable of stimulating TSLP receptor-expressing CD11c + myeloid dendritic cells to secrete chemokines, causing influx and subsequent activation of CD4 + T cells [7]. The strong connection between IL-9 and autoimmunity has also recently been highlighted by the demonstration of its potential role in T-cell-dependent B-cell differentiation, expansion and antibody production [3].…”

Positive association between serum thymic stromal lymphopoietin and anti-citrullinated peptide antibodies in patients with rheumatoid arthritis

“…In addition, blockade of TSLP inhibited arthritis severity in an anti-collagen type II antibody-induced arthritis (CAIA) mouse model [2], and TSLP receptor-deficient mice had less severe arthritis than wild-type mice in T cell-mediated arthritis models [3]. Furthermore, TSLP-primed CD11c 1 myeloid DCs induced Th1 and Th17 activity in addition to Th2 activity in patients with RA [4]. These findings suggest that TSLP plays an important role in the pathophysiology of RA.…”