Neural stem/progenitor cells modulate immune responses by suppressing T lymphocytes with nitric oxide and prostaglandin E2.
We and others have reported that neural stem/progenitor cells (NSCs) may exert direct anti-inflammatory activity. This action has been attributed, in part, to T-cell suppression. However, how T-cells become suppressed by NSCs remains unresolved. In this study, we explored one of these mechanisms and challenged some previously advanced hypotheses regarding underlying NSC-mediated T-cell suppression. We employed an easily observable and manipulatable system in which activated and non-activated T-cells were co-cultured with a stable well-characterized clone of lacZ-expressing murine NSCs. As in previous reports, NSCs were found to inhibit T-cell proliferation. However, this inhibition by NSCs was not due to suppression of T cell activation or induction of apoptosis of T cells during the early activation stage. High levels of nitric oxide (NO) and prostaglandin E2 (PGE2) were induced in the T cells when co-cultured with NSCs. In addition, inducible NOS (iNOS) and microsomal type 1 PGES (mPGES-1) were readily detected in NSCs in co-culture with T-cells, but not at all in NSCs cultured alone or in activated T cells cultured with or without NSCs. This finding suggested that activated T cells induced NO and PGE2 production in the NSCs. Furthermore, T-cell proliferation inhibited by co-culture with the NSCs was significantly restored by inhibitors of NO and PGE2 production. Therefore, NSCs appear to suppress T-cells, at least in part, by NO and PGE2 production which, in turn, would account for the well-documented reduction of central nervous system immunopathology by transplanted NSCs.
Wang
Lei
L
Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849-5525, USA. leiwang@vet.k-state.edu
Shi
Jishu
J
van Ginkel
Frederik W
FW
Lan
Liqiong
L
Niemeyer
Glenn
G
Martin
Douglas R
DR
Snyder
Evan Y
EY
Cox
Nancy R
NR
D000818:Animals; D002450:Cell Communication / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology*; D018920:Coculture Techniques; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004660:Encephalitis / Q000276:immunology / Q000503:physiopathology / Q000628:therapy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D007108:Immune Tolerance / Q000276:immunology*; D007111:Immunity, Cellular; D019746:Intramolecular Oxidoreductases / Q000276:immunology / Q000378:metabolism; D007763:Lac Operon; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone