Invariant natural killer T cells are natural regulators of murine spondylarthritis.
OBJECTIVE
To investigate the role of invariant natural killer T (iNKT) cells in TNF(DeltaARE/+) 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 alpha-galactosylceramide/CD1d tetramers and quantitative polymerase chain reaction for the invariant V(alpha)14-J(alpha)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(DeltaARE/+) mice were backcrossed onto J(alpha)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(DeltaARE/+)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(DeltaARE/+) 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.


CONCLUSIONS
This mode of iNKT cell activation represents a natural counterregulatory mechanism for the dampening of TNF-driven inflammation.
Ghent University, 9000 Ghent, Belgium.
Peggy
P
Jacques
Koen
K
Venken
Katrien
K
Van Beneden
Hamida
H
Hammad
Sylvie
S
Seeuws
Michael B
MB
Drennan
Dieter
D
Deforce
Gust
G
Verbruggen
Maria
M
Apostolaki
George
G
Kollias
Bart N
BN
Lambrecht
Martine
M
De Vos
Dirk
D
Elewaut
D000818:Animals; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015321:Gene Rearrangement; D006706:Homeostasis / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007592:Joint Diseases / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D025241:Spondylarthritis / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics
D014409:Tumor Necrosis Factor-alpha