Abstract
Background and aims: Reports pertaining to the role of regulatory T-cells (Tregs) in immune tolerance of mixed chimeras had varied greatly, depending upon the protocols or strategies used for the creation of hematopoietic chimerism. We aimed to investigate the requirement of Tregs for tolerance maintenance after in utero marrow transplantation.Methods: Hematopoietic chimeras were created by in utero marrow transplantation in the gestational days 14 murine fetus. Skin tolerance was defined by the engraftment of donor skin for more than 4 months in the postnatal life. Tregs were quantified by FoxP3 expression using intracellular staining and real-time PCR. In vivo depletion of Tregs was performed by intraperitoneal anti-CD25 injection in mice with skin tolerance.Results: Tolerant mice had increased Tregs, as evidenced by higher FoxP3 expression among peripheral and splenic CD4+ T-cell populations than non-tolerant and untransplanted mice. Functional assays showed that Tregs from tolerant mice inhibited proliferative alloresponses in a nonspecific manner. However, in vivo depletion of Tregs failed to cause rejection of engrafted donor skins within an observation period of 30 days. Intravenous infusion of 5-7.5×107 naïve host lymphocytes caused rapid rejection of engrafted donor skins within 11-19 days as well as failure to accept secondary donor skins transplanted at least 4 months after lymphocyte infusion.Conclusions: Despite in vivo depletion of increased Tregs in tolerant mice, skin tolerance remained. It argued against a major role of Tregs in the maintenance of skin tolerance following in utero marrow transplantation
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