Multiple sclerosis. Immunomodulatory effects of human astrocytes on T cells.
Using a human culture system, we have previously shown that interferon-gamma-and tumour necrosis factor-alpha-stimulated astrocytes are capable of presenting antigens to T lymphocytes, but do not support antigen-dependent T cell proliferation. To gain further insight into the mechanisms involved in the local regulation of intracerebral T cell responses, we have investigated the effects of astrocytes on T cell proliferation induced by peripheral blood-derived mononuclear cells (PBMC). We found that astrocytes derived from human embryonic brain were able to suppress PBMC-dependent proliferation of antigen-specific, CD4+ T cell lines. Interferon-gamma production by PBMC-stimulated T cells was also suppressed by astrocytes, and this inhibition was seen as early as 6 h after initiation of co-culture. The inhibitory effect was observed in the presence of both HLA matched and mismatched astrocytes and was mediated by astrocyte-derived soluble factor(s) rather than by direct cellular contact. Inhibition of T cell proliferation was incompletely reverted by indomethacin, suggesting that prostaglandins were partially involved in the suppressive effect. The cytotoxic mediator nitric oxide was not involved in astrocyte-mediated inhibition. These observations led us to further investigate the contribution of other mediators known to down-regulate inflammatory processes. Our astrocyte cultures did not synthesize interleukin (IL)-4 or IL-10, whereas they secreted both the latent and active forms of transforming growth factor-beta 2. Transforming growth factor-beta was, however, found not to participate in astrocyte-induced inhibition in vitro. The inhibitory properties of human astrocytes may contribute to confinement of inflammatory lesions in multiple sclerosis and other inflammatory diseases of the central nervous system.
Meinl
E
E
Department of Neuroimmunology, Max-Planck-Institute of Psychiatry, Martinsried, Germany.
Aloisi
F
F
Ertl
B
B
Weber
F
F
de Waal Malefyt
R
R
Wekerle
H
H
Hohlfeld
R
R
D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000276:immunology; D002455:Cell Division; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology
D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D007371:Interferon-gamma