Open AccessInvariant natural killer T cells are natural regulators of murine spondylarthritis
Author(s) -
Jacques Peggy,
Venken Koen,
Van Beneden Katrien,
Hammad Hamida,
Seeuws Sylvie,
Drennan Michael B.,
Deforce Dieter,
Verbruggen Gust,
Apostolaki Maria,
Kollias George,
Lambrecht Bart N.,
De Vos Martine,
Elewaut Dirk
Publication year - 2010
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.27324
Subject(s) - cd1d , natural killer t cell , immunology , cytokine , bone marrow , inflammation , tumor necrosis factor alpha , biology , immune system , medicine , t cell
Objective To investigate the role of invariant natural killer T (iNKT) cells in TNF ΔARE/+ mice, an animal model of spondylarthritis (SpA) with both gut and joint inflammation. Methods The frequency and activation of iNKT cells were analyzed on mononuclear cells from the lymph nodes and livers of mice, using flow cytometry with α‐galactosylceramide/CD1d tetramers and quantitative polymerase chain reaction for the invariant V α 14–J α 18 rearrangement. Bone marrow–derived dendritic cells (DCs) were obtained by expansion of primary cells with granulocyte–macrophage colony‐stimulating factor followed by coculture with iNKT cell hybridomas, and interleukin‐2 release into the cocultures was then measured by enzyme‐linked immunosorbent assay (ELISA). Cytokine levels were determined by ELISA or cytometric bead array analyses of freshly isolated DCs and iNKT cells in mixed cocultures. TNF ΔARE/+ mice were backcrossed onto J α 18 −/− and CD1d −/− mice, and disease onset was evaluated by clinical scoring, positron emission tomography, and histology. CD1d levels were analyzed on mononuclear cells in paired blood and synovial fluid samples from patients with SpA compared with healthy control subjects. Results In the absence of iNKT cells, symptoms of gut and joint inflammation in TNF ΔARE/+ mice were aggravated. Invariant NKT cells were activated during the course of the disease. This was linked to an enrichment of inflammatory DCs, characterized by high levels of CD1d, particularly at draining sites of inflammation. A similar increase in CD1d levels was observed on DCs from patients with SpA. Inflammatory DCs from TNF ΔARE/+ mice stimulated iNKT cells to produce immunomodulatory cytokines, in the absence of exogenous stimulation. Prolonged, continuous exposure, but not short‐term exposure, to tumor necrosis factor (TNF) was found to be responsible for the enhanced DC–NKT cell crosstalk. Conclusion This mode of iNKT cell activation represents a natural counterregulatory mechanism for the dampening of TNF‐driven inflammation.