Astrocyte-induced regulatory T cells mitigate CNS autoimmunity.
Although astrocytes presumably participate in maintaining the immune privilege of the central nervous system (CNS), the mechanisms behind their immunoregulatory properties are still largely undefined. In this study, we describe the development of regulatory T cells upon contact with astrocytes. Rat T cells pre-incubated with astrocytes completely lost the ability to proliferate in response to mitogenic stimuli. The cells were blocked in G0/G1 phase of the cell cycle, expressed less IL-2R, and produced significantly lower amounts of interferon-gamma (IFN-gamma), but not interleukin-2 (IL-2), IL-10, or tumor necrosis factor (TNF). These anergic cells completely prevented mitogen-induced growth of normal T lymphocytes, as well as CNS antigen-driven proliferation of autoreactive T cells. The suppressive activity resided in both CD4+ and CD8+ T-cell compartments. Heat-sensitive soluble T-cell factors, not including transforming growth factor-beta (TGF-beta) or IL-10, were solely responsible for the observed suppression, as well as for the transfer of suppressive activity to normal T cells. The administration of astrocyte-induced regulatory T cells markedly alleviated CNS inflammation and clinical symptoms of CNS autoimmunity in rats with experimental allergic encephalomyelitis. Finally, the cells with suppressive properties were readily generated from human lymphocytes after contact with astrocytes. Taken together, these data indicate that astrocyte-induced regulatory T cells might represent an important mechanism for self-limitation of excessive inflammation in the brain.
Trajkovic
Vladimir
V
Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia and Montenegro.
Vuckovic
Olivera
O
Stosic-Grujicic
Stanislava
S
Miljkovic
Djordje
D
Popadic
Dusan
D
Markovic
Milos
M
Bumbasirevic
Vladimir
V
Backovic
Aleksandar
A
Cvetkovic
Ivana
I
Harhaji
Ljubica
L
Ramic
Zorica
Z
Mostarica Stojkovic
Marija
M
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000276:immunology*; D020274:Autoimmune Diseases of the Nervous System / Q000276:immunology* / Q000503:physiopathology; D002450:Cell Communication / Q000276:immunology*; D002453:Cell Cycle / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004660:Encephalitis / Q000276:immunology / Q000503:physiopathology / Q000628:therapy; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000503:physiopathology / Q000628:therapy; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008934:Mitogens / Q000494:pharmacology; D051381:Rats; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation
D016207:Cytokines; D008934:Mitogens