title: Ligand-dependent inhibition of CD1d-restricted NKT cell development in mice transgenic for the activating receptor Ly49D.
abstract: 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-Dd to determine the importance of these signaling interplays in NKT cell development. Ly49D/H2-Dd 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-Dd 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.
authors.affiliation: Ludwig Institute for Cancer Research, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland. hughrobson.macdonald@isrec.unil.ch
authors.forename: Roger B
authors.initials: RB
authors.lastname: Voyle
authors.forename: Friedrich
authors.initials: F
authors.lastname: Beermann
authors.forename: Rosemary K
authors.initials: RK
authors.lastname: Lees
authors.forename: Jens
authors.initials: J
authors.lastname: Schümann
authors.forename: Jacques
authors.initials: J
authors.lastname: Zimmer
authors.forename: Werner
authors.initials: W
authors.lastname: Held
authors.forename: H Robson
authors.initials: HR
authors.lastname: MacDonald
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D018949:Antigens, CD1 / Q000502:physiology*; D055610:Antigens, CD1d; D000950:Antigens, Ly / Q000737:chemistry / Q000502:physiology*; D006183:H-2 Antigens / Q000502:physiology*; D064532:Histocompatibility Antigen H-2D; D007694:Killer Cells, Natural / Q000502:physiology*; D037181:Lectins, C-Type; D008024:Ligands; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D055650:NK Cell Lectin-Like Receptor Subfamily A; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology; D055630:Receptors, NK Cell Lectin-Like
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018949:Antigens, CD1; D055610:Antigens, CD1d; D000950:Antigens, Ly; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; C527088:Klra1 protein, mouse; C527092:Klra4 protein, mouse; D037181:Lectins, C-Type; D008024:Ligands; D008565:Membrane Proteins; D055650:NK Cell Lectin-Like Receptor Subfamily A; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011971:Receptors, Immunologic; D055630:Receptors, NK Cell Lectin-Like; C110546:TYROBP protein, human