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24-JQ TCR Supports the Development of CD1d-Dependent NK1.1+ and NK1.1- T Cells in Transgenic Mice 1
* Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland;
Cancer Immunotherapy and Gene Therapy Program, DIBIT, H. San Raffaele Scientific Institute, Milan, Italy;
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92121; and
Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland
A sizable fraction of T cells expressing the NK cell marker NK1.1 (NKT cells) bear a very conserved TCR, characterized by homologous invariant (inv.) TCR V
24-JQ and V14-J18 rearrangements in humans and mice, respectively, and are thus defined as inv. NKT cells. Because human inv. NKT cells recognize mouse CD1d in vitro, we wondered whether a human inv. V24 TCR could be selected in vivo by mouse ligands presented by CD1d, thereby supporting the development of inv. NKT cells in mice. Therefore, we generated transgenic (Tg) mice expressing the human inv. V24-JQ TCR chain in all T cells. The expression of the human inv. V24 TCR in TCR C-/- mice indeed rescues the development of inv. NKT cells, which home preferentially to the liver and respond to the CD1d-restricted ligand -galactosylceramide (-GalCer). However, unlike inv. NKT cells from non-Tg mice, the majority of NKT cells in V24 Tg mice display a double-negative phenotype, as well as a significant increase in TCR V
7 and a corresponding decrease in TCR V8.2 use. Despite the forced expression of the human CD1d-restricted TCR in C-/- mice, staining with mCD1d--GalCer tetramers reveals that the absolute numbers of peripheral CD1d-dependent T lymphocytes increase at most by 2-fold. This increase is accounted for mainly by an increased fraction of NK1.1- T cells that bind CD1d--GalCer tetramers. These findings indicate that human inv. V24 TCR supports the development of CD1d-dependent lymphocytes in mice, and argue for a tight homeostatic control on the total number of inv. NKT cells. Thus, human inv. V24 TCR-expressing mice are a valuable model to study different aspects of the inv. NKT cell subset.
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