Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals.
Journal: 2005/March - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
Abstract:
Natural killer (NK) cells are an important component of the innate immune response against viral infections. NK cell-mediated cytolytic activity is defective in HIV-infected individuals with high levels of viral replication. In the present study, we examined the phenotypic and functional characteristics of an unusual CD56(-)/CD16(+) (CD56(-)) NK subset that is greatly expanded in HIV-viremic individuals. The higher level of expression of inhibitory NK receptors and the lower level of expression of natural cytotoxicity receptors observed in the CD56(-) NK fraction compared with that of CD56(+) NK cells was associated with extremely poor in vitro cytotoxic function of this subset. In addition, the secretion of certain cytokines known to be important in initiating antiviral immune responses was markedly reduced in the CD56(-), as compared with the CD56(+) NK cell subset. These data suggest that the expansion of this highly dysfunctional CD56(-) NK cell subset in HIV-viremic individuals largely accounts for the impaired function of the total NK cell population.
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Proc Natl Acad Sci U S A 102(8): 2886-2891

Characterization of CD56<sup>–</sup>/CD16<sup>+</sup> natural killer (NK) cells: A highly dysfunctional NK subset expanded in HIV-infected viremic individuals

+2 authors
Laboratory of Immunoregulation and Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Dipartimento di Medicina Sperimentale, University of Genoa, 16132 Genoa, Italy; and Department of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A1
To whom correspondence should be addressed at: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, Building 10, Room 6A08A, MSC 1576, Bethesda, MD 20892. E-mail: vog.hin.diain@oilivamd.
Contributed by Anthony S. Fauci, January 4, 2005
Contributed by Anthony S. Fauci, January 4, 2005

Abstract

Natural killer (NK) cells are an important component of the innate immune response against viral infections. NK cell-mediated cytolytic activity is defective in HIV-infected individuals with high levels of viral replication. In the present study, we examined the phenotypic and functional characteristics of an unusual CD56/CD16 (CD56) NK subset that is greatly expanded in HIV-viremic individuals. The higher level of expression of inhibitory NK receptors and the lower level of expression of natural cytotoxicity receptors observed in the CD56 NK fraction compared with that of CD56 NK cells was associated with extremely poor in vitro cytotoxic function of this subset. In addition, the secretion of certain cytokines known to be important in initiating antiviral immune responses was markedly reduced in the CD56, as compared with the CD56 NK cell subset. These data suggest that the expansion of this highly dysfunctional CD56 NK cell subset in HIV-viremic individuals largely accounts for the impaired function of the total NK cell population.

Keywords: cytokines, cytotoxicity, inhibitory NK receptors, killer immunoglobulin-like receptors, natural cytotoxicity receptors
Abstract

Natural killer (NK) cells, which account for up to 15% of peripheral blood lymphocytes, are well known as important effectors of the innate immune system (1, 2). In addition, NK cells are an important source of cytokines that regulate hematopoiesis and link the innate to the adaptive immune response through a bidirectional cross-talk with dendritic cells (3, 4).

NK cells are able to lyse tumor and virally infected cells without prior sensitization while sparing normal cells that express adequate levels of MHC of class I molecules (MHC-I). This cytolytic function is under the dominant control of a heterogeneous family of inhibitory NK receptors (iNKRs) that bind specifically to certain allelic forms of HLA of class I (HLA-I). In humans, the iNKRs are divided into two different groups: (i) killer immunoglobulin-like receptors (KIRs); (ii) LIR1/ILT2 and NKG2A/CD94, which belong to the family of the C-type lectin proteins. Diminution or absence of expression of HLA-I molecules on the cell surface because of viral infection or tumor transformation results in reduced engagement of iNKRs; loss of this dominant-negative signal in turn allows a large group of activating NK receptors and coreceptors to trigger cytolytic activity (57).

The role of NK cells in the course of HIV-1 infection remains to be fully elucidated; however, the effect of HIV infection on NK cell function has been increasingly delineated in recent years. It is well documented that NK cells isolated from HIV-infected individuals are impaired in their ability to kill HIV-1-infected autologous cells, as well as tumor cell lines (811). More recently, numerous studies have characterized the effects of HIV viremia on NK cell phenotype and function. In this regard, it has been demonstrated that the expression and function of most major iNKRs are either maintained or significantly increased on the surface of NK cells in viremic patients (12, 13), and a direct correlation has been reported between these findings and levels of HIV viremia (14). Moreover, the expression of natural cytotoxicity receptors (NCRs), NKp46, NKp30, and NKp44, is markedly decreased among viremic individuals, along with a concomitant decrease in NK cytolytic activity (13, 15). In addition, HIV viremia affects the capacity of NK cells to secrete CC-chemokines, which are well known as suppressors of HIV replication ex vivo (16, 17). Finally, the expansion of an unusual CD56/CD16 (CD56) NK cell subset has been associated with high HIV viral loads (10, 13, 18). The successful suppression of HIV replication below detectable levels after treatment with effective antiretroviral therapy results in considerable improvement of NK cell cytotoxicity, cytokine secretion, NK cell receptor expression and function (13), and the restoration of normal CD56 expression (19).

The present study characterizes the phenotypic and functional characteristics of the CD56 NK subset isolated from HIV-1-viremic individuals. This population exhibited significantly lower cytolytic activity and ability to secrete cytokines, as well as more dramatic abnormalities in the expression and function of NK activating and inhibiting receptors when compared with the CD56 NK cell subset from the same individuals. These data suggest that impairments observed in the total NK population of HIV-viremic individuals are largely due to elevated frequencies of this highly dysfunctional CD56 NK cell subset.

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Acknowledgments

This work is dedicated to the memory of Angelo Mavilio. We thank the patients for their participation in this study. We also thank Shyam Kottilil for his invaluable assistance in reviewing the manuscript.

Acknowledgments

Notes

Abbreviations: NK, natural killer; iNKRs, inhibitory NK receptors; KIRs, killer immunoglobulin-like receptors; NCRs, natural cytotoxicity receptors; PBMC, peripheral blood mononuclear cell; rIL-2, recombinant IL-2; GM-CSF, granulocyte/macrophage colony-stimulating factor.

Notes
Abbreviations: NK, natural killer; iNKRs, inhibitory NK receptors; KIRs, killer immunoglobulin-like receptors; NCRs, natural cytotoxicity receptors; PBMC, peripheral blood mononuclear cell; rIL-2, recombinant IL-2; GM-CSF, granulocyte/macrophage colony-stimulating factor.

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