Uterine tissue in early human pregnancy is characterized by extensive vascular remodeling, invasion of fetal trophoblast cells, and by an abundance of maternal natural killer (NK) cells. Trophoblast cells express membrane-bound and soluble isoforms of the non-classical major histocompatibility class I molecule HLA-G. How NK-trophoblast cell interactions influence vascular remodeling is unknown. Signaling from endosomes is emerging as a mechanism by which selected receptors provide sustained signals distinct from those generated at the plasma membrane. The activity of natural killer (NK) cells, which are important effectors of innate immunity and regulators of adaptive immunity, is controlled primarily by receptors that are at the cell surface. Here we show that cytokine secretion by resting human NK cells is induced by soluble, but not solid-phase antibodies to the killer cell immunoglobulin-like receptor (KIR) 2DL4, a receptor for HLA-G. KIR2DL4 was constitutively internalized into Rab5-positive compartments by a dynamin-dependent process. Soluble HLA-G was endocytosed into KIR2DL4-containing compartments in NK cells and in 293T cells transfected with KIR2DL4. Chemokine secretion induced by KIR2DL4 transfection into 293T cells occurred only with recombinant forms of KIR2DL4 that trafficked to endosomes. The profile of genes upregulated by KIR2DL4 engagement on resting NK cells revealed a pro-inflammatory/pro-angiogenic response. Soluble HLA-G induced secretion of a similar set of cytokines and chemokines. This unique stimulation of resting NK cells by soluble HLA-G, which is endocytosed by KIR2DL4, implies that NK cells may provide useful functions at sites of HLA-G expression, such as promotion of vascularization in maternal decidua during early pregnancy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000842-08
Application #
7303786
Study Section
(LIG)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Bryceson, Yenan T; Long, Eric O (2008) Line of attack: NK cell specificity and integration of signals. Curr Opin Immunol 20:344-52
Long, Eric O (2008) Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol Rev 224:70-84
Bryceson, Yenan T; Rudd, Eva; Zheng, Chengyun et al. (2007) Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients. Blood 110:1906-15
Long, Eric O (2007) Ready for prime time: NK cell priming by dendritic cells. Immunity 26:385-7
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Rajagopalan, Sumati; Bryceson, Yenan T; Kuppusamy, Shanmuga P et al. (2006) Activation of NK cells by an endocytosed receptor for soluble HLA-G. PLoS Biol 4:e9
Rajagopalan, Sumati; Long, Eric O (2005) Understanding how combinations of HLA and KIR genes influence disease. J Exp Med 201:1025-9
Rajagopalan, Sumati; Long, Eric O (2005) Viral evasion of NK-cell activation. Trends Immunol 26:403-5
Bryceson, Y T; Foster, J A; Kuppusamy, S P et al. (2005) Expression of a killer cell receptor-like gene in plastic regions of the central nervous system. J Neuroimmunol 161:177-82
Riteau, Beatrice; Barber, Domingo F; Long, Eric O (2003) Vav1 phosphorylation is induced by beta2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization. J Exp Med 198:469-74

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