Negative regulation of natural killer cell function by EAT-2, a SAP-related adaptor.
EAT-2 is an adaptor expressed in innate immune cells, including natural killer (NK) cells. It is closely related to the adaptor SAP, which regulates signaling lymphocyte activation molecule (SLAM)-related receptors by recruiting the kinase FynT to the receptors. Here we have studied the function of EAT-2 in NK cells by creating mice lacking or overexpressing EAT-2. Like SAP, EAT-2 was associated with the SLAM-related receptor 2B4 in NK cells. However, unlike SAP, EAT-2 was an inhibitor of NK cell function. EAT-2 repressed natural cytotoxicity and interferon-gamma secretion by a mechanism involving tyrosine phosphorylation of its C terminus. We have demonstrated a similar function for the adaptor ERT, a newly identified SAP family member expressed in mouse NK cells. These data identify a previously unknown mechanism of NK cell inhibition. Moreover, they indicate that EAT-2 and SAP have distinct and at times opposing functions in natural immunity.
Roncagalli
Romain
R
Clinical Research Institute of Montréal, Montréal, Québec H2W 1R7, Canada.
Taylor
James E R
JE
Zhang
Shaohua
S
Shi
Xiaochu
X
Chen
Riyan
R
Cruz-Munoz
Mario-Ernesto
ME
Yin
Luo
L
Latour
Sylvain
S
Veillette
André
A
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D007371:Interferon-gamma / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology; D016415:Sequence Alignment; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014443:Tyrosine; D018909:src Homology Domains / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C490007:Cd244a protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C499569:Sh2d1a protein, mouse; C491225:Sh2d1b1 protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family; D014157:Transcription Factors; D014443:Tyrosine; D007371:Interferon-gamma