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HLA Class I Molecules Regulate IFN- Production Induced in NK Cells by Target Cells, Viral Products, or Immature Dendritic Cells through the Inhibitory Receptor ILT2/CD85j¹

Research Unit, Hospital Universitario "La Paz"-Fundación para la Investigación Biomédica Hospital "La Paz", Madrid, Spain

Recent advances support an important role for NK cells in determining immune responses beyond their cytolytic functions, which is supported by their capacity to secrete several cytokines and chemokines. In particular, NK-derived IFN- has proven to be fundamental in shaping adaptive immune responses. Although the role of inhibitory NK receptors (iNKR) in the regulation of cytotoxicity has been widely explored, their involvement in the control of cytokine production has been scarcely analyzed. Specifically, no data are available referring to the role of the iNKR ILT2/CD85j in the regulation of IFN- secretion by NK cells. Published data support a differential regulation of cytotoxicity and cytokine expression. Thus, formal proof of the involvement of HLA class I in regulating the production of cytokines through binding to ILT2/CD85j has been missing. We have determined the response of human NK-92 and primary human ILT2/CD85j⁺ NK cells from healthy donors to target cells expressing or not HLA class I. We found specificities of HLA class I-mediated inhibition of IFN- mRNA expression, protein production, and secretion consistent with the specific recognition by ILT2/CD85j. We also found inhibition of IFN- production by ILT2/CD85j⁺ T cells in response to superantigen stimulation. Furthermore, ligation of ILT2/CD85j inhibited the production of IFN- in response to poly(I:C), and blocking of ILT2/CD85j-HLA class I interactions increased the secretion of IFN- in NK/immature dendritic cell cocultures. The data support a role for self HLA class I in the regulation of IFN- secretion at the mRNA and protein levels by interacting with the iNKR ILT2/CD85j.

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 Fundación Mutua Madrileña para la Investigación Biomédica and Grant FIS PI 060441. E.M. is the recipient of a fellowship from Fundación para la Investigación Biomédica Hospital "La Paz."

² Address correspondence and reprint requests to Dr. Teresa Bellón, Research Unit, Hospital Universitario "La Paz," P° Castellana 261, Madrid, Spain. E-mail address: tbellon.hulp{at}salud.madrid.org

³ Abbreviations used in this paper: ADCC, Ab-dependent cell cytotoxicity; DC, dendritic cell; iDC, immature DC; KIR, killer cell Ig-like receptor; FSC, forward light scatter; SSC, side light scatter; iNKR, inhibitory NKR; ILT, Ig-like transcript; LIR/LILR, leukocyte Ig-like receptor; SEB, Staphylococcus enterotoxin B; CBA, cytometric bead array; rh, recombinant human.