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NK1.1⁺ T Cells in the Liver Arise in the Thymus and Are Selected by Interactions with Class I Molecules on CD4⁺CD8⁺ Cells¹

Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, CA 94720

NK1.1⁺ T cells represent a specialized T cell subset specific for CD1d, a nonclassical MHC class I-restricting element. They are believed to function as regulatory T cells. NK1.1⁺ T cell development depends on interactions with CD1d molecules presented by hematopoietic cells rather than thymic epithelial cells. NK1.1⁺ T cells are found in the thymus as well as in peripheral organs such as the liver, spleen, and bone marrow. The site of development of peripheral NK1.1⁺ T cells is controversial, as is the nature of the CD1d-expressing cell that selects them. With the use of nude mice, thymectomized mice reconstituted with fetal liver cells, and thymus-grafted mice, we provide direct evidence that NK1.1⁺ T cells in the liver are thymus dependent and can arise in the thymus from fetal liver precursor cells. We show that the class I⁺ (CD1d⁺) cell type necessary to select NK1.1⁺ T cells can originate from TCR^-/- precursors but not from TCRß^-/- precursors, indicating that the selecting cell is a CD4⁺CD8⁺ thymocyte. 5-Bromo-2'-deoxyuridine-labeling experiments suggest that the thymic NK1.1⁺ T cell population arises from proliferating precursor cells, but is a mostly sessile population that turns over very slowly. Since liver NK1.1⁺ T cells incorporate 5-bromo-2'-deoxyuridine more rapidly than thymic NK1.1⁺ T cells, it appears that liver NK1.1⁺ T cells either represent a subset of thymic NK1.1⁺ T cells or are induced to proliferate after having left the thymus. The results indicate that NK1.1⁺ T cells, like conventional T cells, arise in the thymus where they are selected by interactions with restricting molecules.