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.
The linker for activation of T cells (LAT) and the linker for activation of B cells (LAB/NTAL/LAT2) are integral proteins in receptor coupling to downstream events. Both proteins are expressed in natural killer (NK) cells and LAT is phosphorylated during target cell interactions or ligation of the immunoreceptor tyrosine-based activation motif (ITAM)-coupled CD16. Regardless, Lat(-/-) mice exhibit normal natural and antibody-mediated killing. Here we place both LAT and LAB in the DAP12 pathway of NK cells. Moreover, we unveil a LAT-independent pathway that requires expression of Syk. Mice lacking either LAT or LAB have a skewed Ly49 repertoire, and activated NK cells from Lat(-/-) mice have reduced responses to the ITAM-coupled receptor NK1.1. In contrast, resting Lat(-/-) NK cells show intact NK1.1 responses, whereas NK cells without LAB are hyperactive. Elimination of both adaptors severely reduces NK1.1 signaling under both conditions. Together these data show that NK ITAMs preferentially use a signaling cassette regulated by interplay between LAT and LAB. Activation by interleukin-2 causes a shift to greater dependency on LAT due to suppression of Syk signaling. The overlapping use of multiple adaptors permits fine-tuning of NK-cell ITAM responses over the course of an immune response.
Whittaker
Gillian C
GC
Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick MD, USA.
Burshtyn
Deborah N
DN
Orr
Selinda J
SJ
Quigley
Laura
L
Hodge
Deborah L
DL
Pascal
Véronique
V
Zhang
Weiguo
W
McVicar
Daniel W
DW
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000950:Antigens, Ly / Q000276:immunology*; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D055630:Receptors, NK Cell Lectin-Like; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D000072377:Syk Kinase
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000906:Antibodies; D000950:Antigens, Ly; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; C471359:LAB protein, mouse; C110810:LAT protein, human; C419196:LAT2 protein, human; C491734:Lat protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D010750:Phosphoproteins; D017452:Receptors, IgG; D055630:Receptors, NK Cell Lectin-Like; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse