Genetic evidence supporting selection of the Valpha14i NKT cell lineage from double-positive thymocyte precursors.
Invariant Valpha14i NKT (iNKT) cells are a specialized subset of T lymphocytes with regulatory functions. They coexpress TCRalphabeta and natural killer cell markers. They differentiate through interaction of their Valpha14-Jalpha18 invariant TCRalpha chains with CD1d expressed on double-positive (DP) thymocytes. Although their development has been shown to be thymus dependent, their developmental pathway has not been definitively established. By using genetic analyses, we show here that all iNKT cells are selected from a pool of DP thymocytes. Their development is absolutely dependent on Runx1 and ROR(gamma)t, transcription factors that influence, but are not required for, development of conventional T cells. Our results indicate that even though CD1d binding DP thymocytes have yet to be observed, Valpha14-Jalpha18 rearrangement in these cells is required for development of iNKT cells.
Egawa
Takeshi
T
Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.
Eberl
Gerard
G
Taniuchi
Ichiro
I
Benlagha
Kamel
K
Geissmann
Frederic
F
Hennighausen
Lothar
L
Bendelac
Albert
A
Littman
Dan R
DR
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000276:immunology*; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000276:immunology / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology*; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011518:Proto-Oncogene Proteins; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; C493726:Runx1 protein, mouse; D014157:Transcription Factors