Analysis of the linker for activation of T cells and the linker for activation of B cells in natural killer cells reveals a novel signaling cassette, dual usage in ITAM signaling, and influence on development of the Ly49 repertoire

Abstract

(Fc␥RIIIA, CD16). In addition to CD16, NK cells use a variety of receptors that also use immunoreceptor tyrosine-based activation motifs (ITAM) including human NKp30, NKp44, and NKp46 and murine NK1.1 and NKp46. 1 NK cell activation by these receptor complexes is regulated by the coexpression of a vast array of inhibitory receptors that facilitate the determination of "self" versus "nonself." The best characterized of these are the human killer cell immunoglobulinlike receptors (KIR) and the murine Ly49 family of receptors. 2 Originally described as inhibitory receptors, KIRs and Ly49s bind specific major histocompatibility complex (MHC) Class I molecules expressed on healthy cells and prevent lysis by attenuating signal transduction within the NK cell. The result is efficient lysis only of targets deficient in class I expression or that express high enough levels of activating ligands to override the inhibitory signal.Interestingly, not all KIRs or Ly49s are inhibitory. Several members of each family lack characteristic inhibitory motifs and instead carry charged amino acids in their transmembrane domains that mediate interactions with the ITAM-containing signaling chain, DAP12. 3 Engagement of ITAM-containing receptors in NK cells results in tyrosine phosphorylation of the ITAM, followed by recruitment and activation of protein tyrosine kinases of the Syk/ZAP70 family. This results in increased intracellular ionic calcium, activation of Erk-1 and -2 and ultimately IFN␥ production and/or cytotoxicity. [3][4][5] Studies of signal transduction in T cells have identified a variety of complex adaptor proteins, such as the linker for activation of T cells (LAT), that serve to link proximal tyrosine phosphorylation to downstream events. [6][7][8][9] LAT is expressed in T cells, mast cells, and platelets and is rapidly tyrosine-phosphorylated in response to crosslinking of the T-cell antigen receptor (TcR), the high-affinity receptor for IgE on mast cells or GPVI on platelets. 7,10,11 Upon receptor ligation, LAT associates with a variety of Src homology (SH) 2 domain containing proteins including phospholipase C (PLC)-␥1, Vav, SLP76, Grb2 and the 85 kDa regulatory subunit of PI3 kinase. 7 Consistent with its proposed role as a linker between kinases and downstream effector proteins, cotransfection studies have identified LAT as a substrate of both Syk and ZAP-70 and T cells deficient in LAT are deficient in TcR-mediated Ras activation and calcium mobilization. 8,12 LAT is expressed in NK cells and is phosphorylated upon crosslinking of CD16 or during interaction with susceptible, but not resistant, target cells. 13 The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. 2869BLOOD, 1 OCTOBER 2008 ⅐ VOLUME 112, NUMBER 7For personal use only. on April 30, 2019. by guest www.bloodjournal.org From an al...

Tyrosine Phosphorylation-Independent Regulation of Lipopolysaccharide-Mediated Response by the Transmembrane Adaptor Protein LAB

“…LAB is also expressed in NK cells and macrophages(15, 16). To explore the potential function of LAB in DCs, we first examined the expression of LAB in these cells.…”

Regulation of lymphocyte development and activation by the LAT family of adapter proteins

“…LAB −/− NK cells, on the other hand, have enhanced NK1.1 signaling, recapitulating the negative role of LAB seen in mast cells. Moreover, the deletion of both LAT and LAB in resting and active NK cells causes a severe defect in NK1.1 signaling (84). Natural killer cells, then, are able to utilize LAT and LAB and the interplay between these two can add plasticity to the NK response.…”

Murine natural killer immunoreceptors use distinct proximal signaling complexes to direct cell function

“…This notion is concordant with data from mice lacking various other signaling molecules, although the Ly49 receptor repertoire defects in these mouse models are not as severe. 10,[34][35][36][37][38][39] Thus, SLP-76 may play a central role in orchestrating the positive signals necessary for Ly49 receptor induction. Interestingly, the Ly49 receptor repertoire of LAT1/LAT2 DKO and ADAP KO NK cells is only slightly defective (R.M.M., unpublished observations), suggesting that both pathways contribute to SLP-76-mediated Ly49 receptor acquisition.…”