A critical role for the T cell receptor alpha-chain connecting peptide domain in positive selection of CD1-independent NKT cells

Natural killer T (NKT) cells are a subset of mature alpha beta TCR+ cells t hat co-express NK lineage markers. Whereas most NKT cells express a canonic al V alpha 14/V beta8.2 TCR and are selected by CD1d, a minority of NKT cel ls express a diverse TCR repertoire and develop independently of CD1d. Litt le is known about the selection requirements of CD1d-independent NKT cells. We show here that NKT cells develop in RAG-deficient mice expressing an MH C class II-restricted transgenic TCR (V alpha2/V beta8.1) but only under co nditions that lead to negative selection of conventional T cells. Moreover development of NKT cells in these mice is absolutely dependent upon an inta ct TCR alpha -chain connecting peptide domain, which is required for positi ve selection of conventional T cells via recruitment of the ERK signaling p athway. Collectively our data demonstrate that NKT cells can develop as a r esult of high avidity TCR/MHC class II interactions and suggest that common signaling pathways are involved in the positive selection of CD1d-independ ent NKT cells and conventional T cells.