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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4715-4721.
Prepublished online as a Blood First Edition Paper on February 24, 2005; DOI 10.1182/blood-2004-10-4051.
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IMMUNOBIOLOGY
Ontogeny of CD4+CD25+ regulatory/suppressor T cells in human fetuses
Guillaume Darrasse-Jèze,
Gilles Marodon,
Benoît L. Salomon,
Martin Catala, and
David Klatzmann
From the Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires, Université Pierre et Marie Curie (UPMC)/Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7087, Paris, France; Département de Génétique, Cytogénétique et Embryologie and UPMC/CNRS UMR 7000, Paris, France; and Service de Biothérapie, Hôpital Pitié-Salpêtrière, Paris, France.
Little is known about the ontogeny of naturally occurring CD4+CD25+ regulatory/suppressor T cells that play a major role in maintaining self-tolerance in mice and humans. In rodents, thymectomy on day 3 of life leads to multiple organ-specific autoimmune diseases that can be prevented by adoptive transfer of regulatory T cells, suggesting their neonatal development. We investigated regulatory T-cell ontogeny in 11 human fetuses. Together with the first mature T cells, thymic CD4+CD25+ cells were detected as early as 13 weeks of gestation. Thymic CD25+ cells appeared to be positively selected at the CD4+CD8+CD3hi differentiation stage, as assessed by CD1a and CD69 expression. The proportion of thymic CD4+CD25+ cells appeared quite stable with age, around 6% to 7%, similar to the proportion observed in infant thymi. Extrathymic CD4+CD25+ T cells could hardly be detected at 13 weeks of gestation but were present from week 14 onwards. As adult regulatory T cells, purified CD4+CD25+ fetal cells were anergic and suppressed T-cell proliferative responses; they expressed intracellular cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and Foxp3 mRNA. Altogether, our results indicate that the generation of regulatory/suppressor T cells is consubstantial to the generation of a functional and self-tolerant immune system. (Blood. 2005;105:4715-4721)
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