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CD4+CD28+regulatory T cells in Sjogren's syndrome
Arthritis Research & Therapy volume 3, Article number: 66836 (2000)
SS is a chronic autoimmune exocrinopathy chiefly affecting the salivary and lachrymal glands. The authors have previously established a murine model for SS in NFS/sld mice thymectomised 3 days after birth. The a-fodrin protein was identified as an organ-specific autoantigen in salivary gland tissue. In this study the authors investigate a mechanism of active suppression mediated by regulatory T cells in their model of SS. The authors identify a novel population of regulatory T cells expressing CD28; this key co-stimulatory molecule is expressed on the T cell surface and interacts with ligands B7.1/B7.2 (CD80/86) expressed on the surface of antigen presenting cells (APCs). CD28 delivers the critical 'second signal' to T cells following ligation of the T cell receptor 'first signal'. A number of studies have demonstrated that CD28 co-stimulation of T cells is involved in development of collagen-induced arthritis and experimental autoimmune encephalomyelitis. To investigate active suppression mediated by regulatory T cells involved in autoantigen-specific inhibition of immune responses in a murine model of SS.
Spleen cells from SS mice showed significant autoantigen-specific proliferation in response to fodrin before disease onset, and T cells showed increased expression of activation markers. In vitro stimulated T cells from SS mice showed high levels of interleukin (IL)-4, but low IL-2 and interferon (IFN)-? production before disease onset. A subset of splenic CD4+ T cells expressing low-level CD28; these were present only before disease onset and were CD25-. Addition of anti-CD28 stimulatory antibodies inhibited the splenic T cell response to fodrin. Culture supernatants from unstimulated splenic T cells isolated before disease onset also inhibited proliferation to fodrin autoantigen. Similarly, neutralising antibodies to IL-4 and IL-10 blocked the T cell response to fodrin. As detected by RT-PCR, CD4+CD28low T cells showed increased expression of IL-4, IL-10, IFN-? and transforming growth factor (TGF)-?. Intraperitoneal injection of CD4+CD28low T cells into SS mice was effective in preventing autoimmune lesions, and resulted in decreased titres of autoantibody to fodrin. Splenic CD4+ T cells from SS mice transferred with CD28lowT cells showed decreased expression of activation markers.
A number of studies have shown that autoreactive T cells frequently escape deletion in the thymus and are not tolerized in peripheral lymphoid tissues, but rather persist in the periphery in a state of unresponsiveness. A number of regulatory CD4+ T cell subsets, which are believed to control the autoreactive T cells, have now been described by different groups. Here the authors thymectomise neonatal mice, a technique which is known to impair the migration of regulatory T cells to the periphery (see Additional information), in order to generate a murine model of Sjogren's syndrome (SS). They describe a population of autoantigen-specific peripheral regulatory T cells, identified by low-level CD28 expression. These cells emerge during the first 4 weeks of life and exhibit an immunoregulatory phenotype. The development of disease corresponds with their disappearance. This study raises interesting questions regarding how the CD4+CD28low regulatory T cell subset emerges and why it ultimately fails.
The animal model for SS was established in NFS/sld mice thymectomised 3 days after birth (3d-Tx), in which autoimmune lesions develop at >4 weeks age. Histology was graded on the White and Cassarett scale. Flow cytometric analysis of cells was by standard protocols, as were proliferation assays performed with spleen cells cultured at 5 x 106 cells/well. Cytokine production was assayed by ELISA, intracellular FACS analysis or by RT-PCR. Cell transfer studies were carried out in 3d-Tx NFS/sld mice at 4 weeks of age (n = 7). CD4+CD28low T cells were FACS-sorted from spleen and 5 x 106 cells transferred intraperitoneally in cell transfer experiments.
Shevach EM: Regulatory T cells in autoimmmunity.
Annu Rev Immunol 2000, 18:423-449 (PubMed abstract).
Saegusa K, Ishimaru N, Yanagi K, Haneji N, Nishino M, Azuma M, Saito I, Hayashi Y: Autoantigen-specific CD4+CD28lowT cell subset prevents autoimmune exocrinopathy in murine Sjogren's syndrome. J Immunol. 2000, 165: 2251-2257.