Ontogeny of CD4+CD25+ regulatory/suppressor T cells in human fetuses.
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(+)CD3(hi) 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.
Darrasse-Jèze
Guillaume
G
Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires, Université Pierre et Marie Curie /Centre National de la Recherche Scientifique, Unité Mixte de Recherche, Paris, France.
Marodon
Gilles
G
Salomon
Benoît L
BL
Catala
Martin
M
Klatzmann
David
D
D015703:Antigens, CD / Q000096:biosynthesis; D018949:Antigens, CD1 / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation; D005333:Fetus / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007107:Immune System / Q000502:physiology; D007108:Immune Tolerance; D037181:Lectins, C-Type; D010641:Phenotype; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D013997:Time Factors; D000099192:CD69 Antigens
D015703:Antigens, CD; D018949:Antigens, CD1; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D037181:Lectins, C-Type; D015375:Receptors, Interleukin-2; D000099192:CD69 Antigens; C419393:CD1a antigen