Die Rolle HLA-G positiver regulatorischer T-Zellen in der Pathogenese der Multiplen Sklerose
Zusammenfassung der Projektergebnisse
HLA-G is a non-classical MHC class-Ib molecule with marked inhibitory potential both under physiological and pathophysiological conditions. Structurally, it is similar to that of classical MHC–I molecules however, unlike those it displays limited tissue expression, low allelic polymorphism, and at least 7 isoforms. Although, HLA-G has been shown to be capable of antigen presenting, and induces HLA-G restricted CD8+ T cell response. The emerging concept suggests that HLA-G rather acts as an immune tolerizing molecule. Indeed, HLA-G has been found to be expressed at the sites of “immune privilege” such as fetal-maternal interface (trophoblast cells) where it establishes “semi-allograft” tolerance, or on the cornea and thymus where it contributes in establishing local immune privilege. Furthermore, various tumors express HLA-G to escape tumor specific cytolysis. Others report the inhibition of CD4 and CD8 T cell function by sHLA-G. These results indicate that HLA-G is a key player of immuneregulation, both under physiological (such as pregnancy), and pathological conditions (e.g. cancer, transplantation). Recently, intensive research efforts have been made by our research group and others to reveal the putative in vivo role of HLA-G in immune regulation related to autoimmunity. We described and characterized a naturally occurring HLA-G expressing T-cell population with strong regulatory properties (termed as HLA-G Treg. These cells originate from the thymus and exhibit potent immune suppressive propensity. Within the frame of this study we provided crucial advances to explain how HLA-G plays role during multiple sclerosis pathogenesis. We found significantly increased frequencies of HLA-G Treg cells in the CSF of MS patients and also detected CNS resident HLA-G expressing T cells in brain specimens of MS patients. We also demonstrated elereg vated frequencies of HLA-G Treg cells under acute inflammatory conditions in the CNS of MS patients caused likely by preferential migration of CCR5+ HLA-G Treg cells to the sites of inreg flammation. Moreover, we revealed further details about the mode of action of HLA-G Treg cells and identified IL-10 as crucial soluble factor mediating HLA-G+ Treg suppression. Taken together, our completed study revealed not only novel mechanistic insights about the mode of action of HLA-G Treg cells but also demonstrate the in vivo relevance of HLA-G Treg cells in MS patients to limit autoimmune CNS damage. HLA-G Treg cells seemed to display a hypoproliferative capacity. However, this turns out to be at least partly a survival defect altering proliferation capacity (unpublished observation). The “hypoproliferative” capacity of HLA-G Treg cells could be broken by our in vitro T cell expansion protocol. More detailed in depth analysis of the survival/proliferation behavior of HLA-G Treg cells is ongoing.
Projektbezogene Publikationen (Auswahl)
-
Frequency of Regulatory T Cells is Not Affected by Transient B Cell Depletion Using Anti-CD20 Antibodies in Rheumatoid Arthritis. Open Rheumatol J. 2008;2:81-8
Feuchtenberger M, Müller S, Roll P, Waschbisch A, Schäfer A, Kneitz C, Wiendl H, Tony HP
-
Specific central nervous system recruitment of HLA-G(+) regulatory T cells in multiple sclerosis. Ann Neurol. 2009 Aug;66(2):171-83
Huang YH, Zozulya AL, Weidenfeller C, Metz I, Buck D, Toyka KV, Brück W, Wiendl H
-
T cell suppression by naturally occurring HLA-G-expressing regulatory CD4+ T cells is IL-10-dependent and reversible. J Leukoc Biol. 2009 Aug;86(2):273-81
Huang YH, Zozulya AL, Weidenfeller C, Schwab N, Wiendl H
-
Janus head: the dual role of HLA-G in CNS immunity. Cell Mol Life Sci. 2011 Feb;68(3):407-16
Huang YH, Airas L, Schwab N, Wiendl H
