Negative regulation of natural killer cell function by EAT-2, a SAP-related adaptor

Romain Roncagalli^1, 2, James E R Taylor¹, Shaohua Zhang¹, Xiaochu Shi¹, Riyan Chen¹, Mario-Ernesto Cruz-Munoz¹, Luo Yin³, Sylvain Latour⁴ & André Veillette^1, 5, 6

¹  Clinical Research Institute of Montréal, Montréal, Québec H2W 1R7, Canada.

²  Program in Molecular Biology, University of Montréal, Montréal, Québec H2W 1R7, Canada.

³  International Agency for Research on Cancer, Lyon 69372, France.

⁴  Unité INSERM U429, Hôpital Necker Enfants-Malades, Paris 75015, France.

⁵  Department of Medicine, University of Montréal, Montréal, Québec H3C 3J7, Canada.

⁶  Department of Medicine, McGill University, Montréal, Québec H3G 1Y6, Canada.

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- 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.

	Top