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CD94/NKG2A Inhibits NK Cell Activation by Disrupting the Actin Network at the Immunological Synapse¹

Madhan Masilamani^*, Connie Nguyen^*, Juraj Kabat, Francisco Borrego^* and John E. Coligan^2,*

^* Receptor Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; and Biological Imaging Facility, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

An adequate immune response is the result of the fine balance between activation and inhibitory signals. The exact means by which inhibitory signals obviate activation signals in immune cells are not totally elucidated. Human CD94/NKG2A is an ITIM-containing inhibitory receptor expressed by NK cells and some CD8⁺ T cells that recognize HLA-E. We show that the engagement of this receptor prevents NK cell activation by disruption of the actin network and exclusion of lipid rafts at the point of contact with its ligand (inhibitory NK cell immunological synapse, iNKIS). CD94/NKG2A engagement leads to recruitment and activation of src homology 2 domain-bearing tyrosine phosphatase 1. This likely explains the observed dephosphorylation of guanine nucleotide exchange factor and regulator of actin, Vav1, as well as ezrin-radixin-moesin proteins that connect actin filaments to membrane structures. In contrast, NK cell activation by NKG2D induced Vav1 and ezrin-radixin-moesin phosphorylation. Thus, CD94/NKG2A prevents actin-dependent recruitment of raft-associated activation receptors complexes to the activating synapse. This was further substantiated by showing that inhibition of actin polymerization abolished lipid rafts exclusion at the iNKIS, whereas cholesterol depletion had no effect on actin disruption at the iNKIS. These data indicate that the lipid rafts exclusion at the iNKIS is an active process which requires an intact cytoskeleton to maintain lipid rafts outside the inhibitory synapse. The net effect is to maintain an inhibitory state in the proximity of the iNKIS, while allowing the formation of activation synapse at distal points within the same NK cell.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funds from the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

² Address correspondence and reprint requests to Dr. John E. Coligan, Receptor Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Twinbrook II, Room 205, 12441 Parklawn Drive, Rockville, MD 20852. E-mail: JCOLIGAN{at}niaid.nih.gov

³ Abbreviations used in this paper: Ctx-B, cholera toxin-B; ERM, ezrin-radixin-moesin; KIR, killer cell immunoglobulin-like receptor; MCD, methyl--cyclodextrin; iNKIS, inhibitory NK cell immunological synapse; aNKIS, activation NK cell immunological synapse; pY, phosphotyrosine; SHP-1, src homology 2 domain-bearing tyrosine phosphatase-1; ROI, region of interest; MICA, MHC class I chain-related A.

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