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Article

James R. Carlyle^*, Alison M. Michie^*, Caren Furlonger, Toru Nakano, Michael J. Lenardo^||, Christopher J. Paige^*,, and Juan Carlos Zúñiga-Pflücker^*

From the ^* Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; The Wellesley Hospital Research Institute, Toronto, Ontario M4Y 1J3, Canada; Department of Molecular Cell Biology, Research Institute for Microbial Diseases, Osaka University, Yamada-Oka 3-1, Suita, Osaka 565, Japan; and the ^|| Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Bipotent progenitors for T and natural killer (NK) lymphocytes are thought to exist among early precursor thymocytes. The identification and functional properties of such a progenitor population remain undefined. We report the identification of a novel developmental stage during fetal thymic ontogeny that delineates a population of T/NK-committed progenitors (NK1.1⁺/CD117⁺/CD44⁺/CD25^–). Thymocytes at this stage in development are phenotypically and functionally distinguishable from the pool of multipotent lymphoid-restricted (B, T, and NK) precursor thymocytes. Exposure of multipotent precursor thymocytes or fetal liver– derived hematopoietic progenitors to thymic stroma induces differentiation to the bipotent developmental stage. Continued exposure to a thymic microenvironment results in predominant commitment to the T cell lineage, whereas coculture with a bone marrow–derived stromal cell line results in the generation of mature NK cells. Thus, the restriction point to T and NK lymphocyte destinies from a multipotent progenitor stage is marked by a thymus-induced differentiation step.

J.R. Carlyle is supported by a studentship from the Medical Research Council of Canada (MRC). J.C. Zúñiga-Pflücker is supported by a scholarship from the MRC. This work was funded by grants from the MRC and the National Cancer Institute of Canada.

¹Abbreviations used in this paper: dGuo, deoxyguanosine; DP, double positive; FL, fetal liver; FTLP, fetal thymic lymphoid progenitor; FTNK, fetal thymic NK1.1⁺; FTOC, fetal thymic organ culture; HSA, heat-stable antigen; SCF, stem cell factor; TLP, thymic lymphoid progenitor.

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