| Abstract |
Soluble MHCII (sMHCII) molecules are present in body fluids of healthy individuals and are considered to be involved in the maintenance of self tolerance, and related to various diseases. Many studies have shown that sMHC molecules play an important role in the physiology of disease but it has not yet been clarified whether they are products of the disease or contribute on its progression. Their concentration increases during in vivo antigen-specific tolerogenic stimulation and it was recently shown that exosome-mediated tolerance is MHCII dependent. At the cellular level, sMHCII proteins compete with membrane MHCII for T-cell receptor binding on CD4+ T cells.
Immunoaffinity purification techniques isolated sMHCII antigens from the serum of human serum albumin (HSA)-tolerant mice as a single highly glycosylated protein with a molecular weight of ~60.000, specifically interacting with anti-class II antibodies in Western blotting, ELISA, and acoustic biosensor techniques. Mass spectroscopy analysis showed that these sMHCII proteins were loaded with the tolerogenic peptide as well as multiple self peptides.
At the cellular level, sMHCII suppressed antigen-specific, and to a lesser degree antigen-non-specific, spleen cell proliferation in vitro as well as in vivo. Using, acoystic biosensor techniques, we confirmed the interaction between sMHCII molecules and CD4+ T-cells. SMHCII were able to induced CD25 expression in naive T cells and in T cells activated by antigen-seeded macrophages. In addition, sMHCII decreased CD28 and increased CTLA-4 protein expression, while decreasing interleukin-2 and increasing interleukin-10 production. In this case, sMHCII proteins were shown to decrease ZAP-70 and LAT phosphorylation.
When we compared different tolerization protocols (different days), we concluded that the tolerization mediaded by cells is a late response of the organism and is possible that soluble factors are produced first.
The results presented here for the first time provide evidence for the role of sMHCII proteins in immune response suppression and maintenance of tolerance, revealing novel regulatory mechanisms for immune system manipulation.
In conclusion, the present work demonstrated that sMHCII proteins isolated from HSA-tolerant mouse serum exerted antigen-specific as well as antigen-non-specific suppressive effects on CD4+ T cells which are mediated not only by inhibitory marker expression but also by production of suppressive soluble products (i.e. IL-10).
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Η ανοσοκατασταλτική δράση των διαλυτών MHC class-ΙΙ μορίων του ορού σε CD4+ T-λεμφοκύτταρα
