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© The Rockefeller University Press, 0022-1007/1997/4/1395/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 8, April 21, 1997 1395-1402

Article

Lineage Relationships and Differentiation of Natural Killer (NK) T Cells: Intrathymic Selection and Interleukin (IL)-4 Production in the Absence of NKR-P1 and Ly49 Molecules

Olivier Lantz*, Lama I. Sharara{ddagger}, Florence Tilloy*, Åsa Andersson{ddagger}, and James P. DiSanto{ddagger}

From the * Institut National de la Santé et de la Recherche Medicale U267, Hôpital Paul Brousse, Villejuif 94807, France; and the {ddagger} Institut National de la Santé et de la Recherche Medicale U429, Hôpital Necker, Paris 75743, France

In this report, we have assessed the lineage relationships and cytokine dependency of natural killer (NK) T cells compared with mainstream TCR-{alpha}β T cells and NK cells. For this purpose, we studied common {gamma} chain ({gamma}c)-deficient mice, which demonstrate a selective defect in CD3– NK cell development relative to conventional TCR-{alpha}β T cells. NK thymocytes differentiate in {gamma}c– mice as shown by the normal percentage of TCR Vβ8+ CD4–CD8– cells and the normal quantity of thymic V{alpha}14–J{alpha}281 mRNA that characterize the NK T repertoire. However, {gamma}c-deficient NK thymocytes fail to coexpress the NK-associated markers NKR-P1 or Ly49, yet retain characteristic expression of the cytokine receptors interleukin (IL)-7R{alpha} and IL-2Rβ. Despite these phenotypic abnormalities, {gamma}c– NK thymocytes could produce normal amounts of IL-4. These results define a maturational progression of NK thymocyte differentiation where intrathymic selection and IL-4–producing capacity can be clearly dissociated from the acquisition of the NK phenotype. Moreover, these data suggest a closer ontogenic relationship of NK T cells to TCR-{alpha}β T cells than to NK cells with respect to cytokine dependency. We also failed to detect peripheral NK T cells in these mice, demonstrating that {gamma}c-dependent interactions are required for export and/or survival of NK T cells from the thymus. These results suggest a stepwise pattern of differentiation for thymically derived NK T cells: primary selection via their invariant TCR to confer the IL-4–producing phenotype, followed by acquisition of NK-associated markers and maturation/export to the periphery.

Address correspondence to Dr. James P. DiSanto, INSERM U429, Hôpital Necker, Pavillon Kirmisson, 149 rue de Sèvres, 75743 Paris, France.

1Abbreviations used in this paper: DN, double negative; {gamma}c, common {gamma} chain; HSA, heat-stable antigen; TSLP, thymic stromal cell–derived lymphopoietin.


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