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¹ Ludwig Institute For Cancer Research, Lausanne Branch, University of Lausanne
² Swiss Institute for Experimental Cancer Research, 1066 Epalinges, Switzerland

Address correspondence to H. Robson MacDonald, Ludwig Institute for Cancer Research, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland. Phone: 41-21-692-59-89; Fax: 41-21-653-44-74; E-mail: hughrobson.macdonald{at}isrec.unil.ch

In addition to their CD1d-restricted T cell receptor (TCR), natural killer T (NKT) cells express various receptors normally associated with NK cells thought to act, in part, as modulators of TCR signaling. Immunoreceptor-tyrosine activation (ITAM) and inhibition (ITIM) motifs associated with NK receptors may augment or attenuate perceived TCR signals respectively, potentially influencing NKT cell development and function. ITIM-containing Ly49 family receptors expressed by NKT cells are proposed to play a role in their development and function. We have produced mice transgenic for the ITAM-associated Ly49D and ITIM-containing Ly49A receptors and their common ligand H2-D^d to determine the importance of these signaling interplays in NKT cell development. Ly49D/H2-D^d transgenic mice had selectively and severely reduced numbers of thymic and peripheral NKT cells, whereas both ligand and Ly49D transgenics had normal numbers of NKT cells. CD1d tetramer staining revealed a blockade of NKT cell development at an early precursor stage. Coexpression of a Ly49A transgene partially rescued NKT cell development in Ly49D/H2-D^d transgenics, presumably due to attenuation of ITAM signaling. Thus, Ly49D-induced ITAM signaling is incompatible with the early development of cells expressing semi-invariant CD1d-restricted TCRs and appropriately harmonized ITIM–ITAM signaling is likely to play an important role in the developmental program of NKT cells.

Key Words: NKT cell development • ITAM-containing receptors • ITIM-containing receptors • TCR repertoire • NK receptor repertoire

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