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* Experimental Immunology Unit, Cancer Immunotherapy and Gene Therapy Program, DIBIT, San Raffaele Scientific Institute,
San Raffaele Telethon Institute for Gene Therapy,
Division of Obstetrics and Gynecology, San Raffaele Scientific Institute, Milan;
Laboratory of Neuroimmunology, Fondazione Santa Lucia, Rome, Italy; and
¶ Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany
Conventional MHC-restricted T lymphocytes leave thymus with a naive phenotype and require Ag-dependent stimulation coupled to proliferation to acquire effector functions. Invariant (i)NKT cells are a subset of T lymphocytes considered innate because they display an effector memory phenotype independent of TCR stimulation by foreign Ags. We investigated the effector differentiation program followed by human iNKT cells by studying cells from a relevant set of fetal thymi and umbilical cord blood samples. We find that human fetal iNKT cells have already started a differentiation program that activates the epigenetic and transcriptional control of ifng and il4 genes, leading at birth to cells that express these cytokines upon TCR signaling but independently of proliferation in vitro. Both ex vivo and in vitro analysis of fetal and neonatal iNKT cells delineate an effector differentiation program linked to cell division in vivo, and they identify IL-7 as one of the crucial signals driving this program in the apparent absence of Ag stimulation. Consistent with these data, human fetal and neonatal iNKT cells are hyperresponsive in vitro to IL-7 in comparison to conventional T cells, owing to an increased expression and signaling function of the IL-7 receptor 
-chain. The innate nature of human iNKT cells could thus derive from lineage-specific developmental cues that selectively make these cells efficient IL-7 responders following thymic selection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The study was supported by grants from the Italian Association for Cancer Research, Italian Ministry of Health Ricerca Finalizzata, and Fondazione Cassa di Risparmio delle Provincie Lombarde (to G.C. and P.D.), and in part by Fondazione Telethon (to A.A.).
2 Address correspondence and reprint requests to Dr. Claudia de Lalla, Dr. Paolo Dellabona, and Dr. Giulia Casorati, Experimental Immunology Unit, Cancer Immunotherapy and Gene Therapy Program, DIBIT, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy. E-mail addresses: delalla.claudia{at}hsr.it, dellabona.paolo{at}hsr.it, and casorati.giulia{at}hsr.it
3 Abbreviations used in this paper: iNKT, invariant NKT; GalCer, -galactosyl ceramide; AB, adult blood; CB, umbilical cord blood; CIRE, conserved intronic regulatory element; FT, fetal thymus; TEM, effector memory T; TREC, TCR excision circle.
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