Expression of heme oxygenase-1 in neural stem/progenitor cells as a potential mechanism to evade host immune response.
Besides their therapeutic benefit as cell source, neural stem/progenitor cells (NSPCs) exhibit immunosuppressive properties of great interest for modulating immune response in the central nervous system. To decipher the mechanisms of NSPC-mediated immunosuppression, activated T cells were exposed to NSPCs isolated from fetal rat brains. Analyses revealed that NSPCs inhibited T-cell proliferation and interferon-gamma production in a dose-dependent manner. A higher proportion of helper T cells (CD4+ T cells) was found in the presence of NSPCs, but analyses of FoxP3 population indicated that T-cell suppression was not secondary to an induction of suppressive regulatory T cells (FoxP3+ CD4+ CD25+). Conversely, induction of the high affinity interleukin-2 (IL-2) receptor (CD25) and the inability of IL-2 to rescue T-cell proliferation suggest that NSPCs display immunosuppressive activity without affecting T-cell activation. Cultures in Transwell chambers or addition of NSPC-conditioned medium to activated T cells indicated that part of the suppressive activity was not contact dependent. We therefore searched for soluble factors that mediate NSPC immunosuppression. We found that NSPCs express several immunosuppressive molecules, but the ability of these cells to inhibit T-cell proliferation was only counteracted by heme oxygenase (HO) inhibitors in association or not with nitric oxide synthase inhibitors. Taken together, our findings highlight a dynamic crosstalk between NSPCs and T lymphocytes and provide the first evidence of an implication of HO-1 in mediating the immunosuppressive effects of the NSPCs.
INSERM, U643, Nantes, France.
Virginie
V
Bonnamain
Elodie
E
Mathieux
Reynald
R
Thinard
Paméla
P
Thébault
Véronique
V
Nerrière-Daguin
Xavier
X
Lévêque
Ignacio
I
Anegon
Bernard
B
Vanhove
Isabelle
I
Neveu
Philippe
P
Naveilhan
D000818:Animals; D001921:Brain / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology; D049109:Cell Proliferation; D018920:Coculture Techniques; D004622:Embryo, Mammalian; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D058953:Neural Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D051547:Heme Oxygenase-1