Autoantigen-specific CD4(+)CD28(low) T cell subset prevents autoimmune exocrinopathy in murine Sjogren's syndrome

Organ-specific autoimmune exocrinopathy resembling Sjogren's syndrome (SS) that spontaneously develops in NFS/sld mutant mice thymectomized 3 day afte r birth is dependent on Th1-type CD4(+) T cells, We previously reported tha t a cleavage product of 120-kDa alpha-fodrin may be an important autoantige n in the pathogenesis of SS in both an animal model and the patients. We de monstrate that in an animal model of SS with overt exocrinopathy, a unique CD4(+) T cell subset expressing CD28(low) is dramatically increased in sple en cells before the disease onset, but that the CD4(+) T cells of diseased mice were virtually all CD28(high). We found that the spleen cells in these mice before the disease onset showed a significant increase in autoantigen -specific T cell proliferation. Analysis of in vitro cytokine production by spleen cells indicated, before the disease onset, severely impaired produc tion of IL-2 and IFN-gamma in the animal model, whereas high levels of IL-4 were observed. Expression of cytokine genes, including IL-4, IL-10, and TG F-beta, was detected in FACS-sorted CD4(+)CD28(low) T cells by RT-PCR analy sis. Transfer of CD4(+)CD28(low) T cells into the animal model actually pre vented the development of autoimmune lesions including autoantibody product ion. These results suggest that a CD4(+)CD28(low) T cell subset that is con tinuously activated by an organ-specific autoantigen may play a regulatory role in the development of organ-specific autoimmune disease in an animal m odel of SS.