NKT cells aggravate arthritis by blocking TGF-β.

The dark side of NKT cells is revealed in a new study showing that they contribute to autoimmune arthritis in mice. On page 41, Kim et al. find that arthritis is worse in joints that are invaded by NKT cells.

NKT cells are innate immune cells that express both NK and T cell markers, and are protective in many other models of autoimmune disease. The authors tested NKT function in K/BxN mice—an established model of rheumatoid arthritis. These mice spontaneously develop a progressive inflammatory disease that is caused by the deposition of autoantibodies in joints. Disease can be transferred to healthy recipient mice by injecting them with K/BxN serum.Kim et al. now show that mice lacking NKT cells develop only mild joint inflammation when given K/BxN serum. This protection was reversed if the deficient mice were reconstituted with NKT cells.

The nonarthritic mice lacking NKT cells had high levels of TGF-β1 in their joints, which dropped as soon as the NKT cells arrived on the scene. Blocking TGF-β1 in the same NKT cell–deficient mice increased joint swelling, suggesting a protective role for this cytokine. Suppression of TGF-β1 production depended on the ability of the NKT cells to produce both IL-4 and IFN-γ.

Many questions remain unanswered. Future studies might reveal which cells produce the TGF-β1 in the joints, how TGF-β1 prevents arthritis, what attracts NKT cells to the joint, and how NKT cells suppress TGF-β1 production.