Interactions of NK cell receptor KIR3DL1*004 with chaperones and conformation-specific antibody reveal a functional folded state as well as predominant intracellular retention.
Variable interaction between the Bw4 epitope of HLA-B and the polymorphic KIR3DL1/S1 system of inhibitory and activating NK cell receptors diversifies the development, repertoire formation, and response of human NK cells. KIR3DL1*004, a common KIR3DL1 allotype, in combination with Bw4(+) HLA-B, slows progression of HIV infection to AIDS. Analysis in this study of KIR3DL1*004 membrane traffic in NK cells shows this allotype is largely misfolded but stably retained in the endoplasmic reticulum, where it binds to the chaperone calreticulin and does not induce the unfolded protein response. A small fraction of KIR3DL1*004 folds correctly and leaves the endoplasmic reticulum to be expressed on the surface of primary NK and transfected NKL cells, in a form that can be triggered to inhibit NK cell activation and secretion of IFN-γ. Consistent with this small proportion of correctly folded molecules, trace amounts of MHC class I coimmunoprecipitated with KIR3DL1*004. There was no indication of any extensive intracellular interaction between unfolded KIR3DL1*004 and cognate Bw4(+) HLA-B. A similarly limited interaction of Bw4 with KIR3DL1*002, when both were expressed by the same cell, was observed despite the efficient folding of KIR3DL1*002 and its abundance on the NK cell surface. Several positions of polymorphism modulate KIR3DL1 abundance at the cell surface, differences that do not necessarily correlate with the potency of allotype function. In this context, our results suggest the possibility that the effect of Bw4(+) HLA-B and KIR3DL1*004 in slowing progression to AIDS is mediated by interaction of Bw4(+) HLA-B with the small fraction of cell surface KIR3DL1*004.
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Sabrina B
SB
Taner
Marcelo J
MJ
Pando
Allison
A
Roberts
Jennifer
J
Schellekens
Steven G E
SG
Marsh
Karl-Johan
KJ
Malmberg
Peter
P
Parham
Frances M
FM
Brodsky
D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism*; D037282:Calreticulin / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015235:HLA-B Antigens / Q000378:metabolism; D006801:Humans; D007424:Intracellular Fluid / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D008024:Ligands; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D017510:Protein Folding; D021381:Protein Transport / Q000276:immunology; D058767:Protein Unfolding; D054341:Receptors, KIR3DL1 / Q000737:chemistry / Q000378:metabolism*; D013312:Stress, Physiological / Q000276:immunology
D000911:Antibodies, Monoclonal; D037282:Calreticulin; D015235:HLA-B Antigens; C042388:HLA-Bw4 antigen; C515083:KIR3DL1 protein, human; D008024:Ligands; D018832:Molecular Chaperones; D054341:Receptors, KIR3DL1