Submitted November 2, 2007
Accepted May 19, 2008
Analysis of the linker for activation of T cells (LAT) and the linker for activation of B cells (LAB) in natural killer cells reveals a novel signaling cassette, dual usage in ITAM signaling, and influence on development of the Ly49 repertoire
Gillian C Whittaker, Deborah N Burshtyn, Selinda J Orr, Laura Quigley, Deborah L Hodge, Veronique Pascal, Weiguo Zhang, and Daniel W. McVicar*
Cancer and Inflammation Program, National Cancer Institute, Frederick, MD, United States
Department of Medical Microbiology and Immunology, Unversity of Alberta, Edmonton, Alberta, Canada
Department of Microbiology and Immunology, Duke University Medical School, Durham, NC, United States
* Corresponding author; email: mcvicard{at}mail.nih.gov.
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 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 whilst 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 utilize a signaling cassette regulated by interplay between LAT and LAB. Activation by IL-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
