Autoantigen-specific CD4+CD28low 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 after birth is dependent on Th1-type CD4(+) T cells, We previously reported that a cleavage product of 120-kDa alpha-fodrin may be an important autoantigen in the pathogenesis of SS in both an animal model and the patients. We demonstrate that in an animal model of SS with overt exocrinopathy, a unique CD4(+) T cell subset expressing CD28(low) is dramatically increased in spleen 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 production 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 TGF-beta, was detected in FACS-sorted CD4(+)CD28(low) T cells by RT-PCR analysis. Transfer of CD4(+)CD28(low) T cells into the animal model actually prevented the development of autoimmune lesions including autoantibody production. These results suggest that a CD4(+)CD28(low) T cell subset that is continuously activated by an organ-specific autoantigen may play a regulatory role in the development of organ-specific autoimmune disease in an animal model of SS.