Although (self)antigen-directed T cells are thought to be key mediators of many autoimmune diseases, a functionally distinct population of CD4⁺ T cells – T regulatory cells (Treg cells) – dominantly inhibit induction and progression of autoimmunity, as demonstrated in several autoimmune models. In humans the presence of Treg cells has been shown, but their role in autoimmune disease is not known. Likewise, no (auto)antigens recognized by Treg cells have yet been identified at the molecular level. The aim of these studies was to gain a better understanding of the identity of (auto)antigens recognized by Treg cells.

When analyzing the natural T cell response against a candidate autoantigen in rheumatoid arthritis (RA), namely human cartilage gp-39 (HC gp-39), we found that healthy donors, although displaying a typical Th1 reaction against a mixture of recall antigens, reacted against HC gp-39 by producing IL-10. The IL-10 production was mediated by CD4⁺ T cells. When HC gp-39-directed immunity of RA patients was analyzed, a marked contrast was observed as Th1-like reactivity was observed in a substantial number of patients as determined by the production of IFN-γ. More importantly, we found that HC gp-39-directed immunity in healthy donors inhibits the T cell response against a mixture of recall antigens. Likewise, HC gp-39-specific immunity as well as HC gp-39-directed, IL-10-producing CD4⁺ T cell lines were able to suppress MHC class I-restricted CTL reactivity.

Together, these data point to a disease-associated bias in the type of T cell response against HC gp-39, and identify HC gp-39 as a naturally occurring autoantigen that is recognized by Treg cells in humans.