NK cell recognition of non-classical HLA class I molecules

Natural killer (NK) cells provide a first line of defense against viral infections. The mechanisms by which NK cells recognize and eliminate infected cells are still largely unknown. To test whether target cell elements contribute to NK cell recognition of virus-infected cells, human NK cells were cloned from two unrelated donors and assayed for their ability to kill normal autologous or allogeneic cells before and after infection by human herpesvirus 6 (HHV-6), a T-lymphotropic herpesvirus. Of 132 NK clones isolated from donor 1, all displayed strong cytolytic activity against the NK-sensitive cell line K562, none killed uninfected autologous T cells, and 65 (49%) killed autologous T cells infected with HHV-6. A panel of representative NK clones from donors 1 and 2 was tested on targets obtained from four donors. A wide heterogeneity was observed in the specificity of lysis of infected target cells among the NK clones. Some clones killed none, some killed only one, and others killed more than one of the different HHV-6-infected target cells. Killing of infected targets was not due to complete absence of class I molecules because class I surface levels were only partially affected by HHV-6 infection. Thus, target cell recognition is not controlled by the effector NK cell alone, but also by polymorphic elements on the target cell that restrict NK cell recognition. Furthermore, NK clones from different donors display a variable range of specificities in their recognition of infected target cells.

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Back signaling of HLA class I molecules and T/ NK cell receptor ligands in epithelial cells reflects the rejection‐specific microenvironment in renal allograft biopsies

American Journal of Transplantation ◽

10.1111/ajt.15417 ◽

2019 ◽

Vol 19 (10) ◽

pp. 2692-2704 ◽

Cited By ~ 5

Author(s):

Johanna Egelkamp ◽

Evgeny Chichelnitskiy ◽

Jenny F. Kühne ◽

Franziska Wandrer ◽

Kerstin Daemen ◽

...

Keyword(s):

Epithelial Cells ◽

Renal Allograft ◽

Nk Cell ◽

Hla Class I ◽

Cell Receptor ◽

Class I ◽

Receptor Ligands ◽

Hla Class I Molecules ◽

Nk Cell Receptor

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Functional Resemblance between the Ig-Related NK Cell Receptors Specific for HLA Class I Molecules and the CD94 C-Type Lectin

Molecular Basis of NK Cell Recognition and Function - Chemical Immunology and Allergy ◽

10.1159/000319338 ◽

1996 ◽

pp. 116-134 ◽

Cited By ~ 3

Author(s):

Miguel López-Botet ◽

Juan J. Pérez-Villar ◽

Marta Carretero ◽

Antonio Rodríguez ◽

Ignacio Melero

Keyword(s):

Nk Cell ◽

Hla Class I ◽

Class I ◽

Cell Receptors ◽

Nk Cell Receptors ◽

Hla Class I Molecules

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Analysis of natural killer cells in TAP2-deficient patients: expression of functional triggering receptors and evidence for the existence of inhibitory receptor(s) that prevent lysis of normal autologous cells

Blood ◽

10.1182/blood.v99.5.1723 ◽

2002 ◽

Vol 99 (5) ◽

pp. 1723-1729 ◽

Cited By ~ 47

Author(s):

Massimo Vitale ◽

Jacques Zimmer ◽

Roberta Castriconi ◽

Daniel Hanau ◽

Lionel Donato ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Antigen Processing ◽

Nk Cell ◽

Hla Class I ◽

Surface Expression ◽

Class I ◽

Inhibitory Receptor ◽

Surface Receptors ◽

Hla Class I Molecules

Natural killer (NK) cells are characterized by the ability to kill cells that lack HLA class I molecules while sparing autologous normal (HLA class I+) cells. However, patients with transporter-associated antigen processing (TAP) deficiency, though displaying strong reductions of HLA class I surface expression, in most instances do not experience NK-mediated autoimmune phenomena. A possible mechanism by which TAP−/− NK cells avoid autoreactivity against autologous HLA class I–deficient cells could be based on either quantitative or qualitative defects of surface receptors involved in NK cell triggering. In this study we show that NK cells derived from 2 patients with TAP2−/− express normal levels of all known triggering receptors. As revealed by the analysis of polyclonal and clonal NK cells, these receptors display normal functional capabilities and allow the killing of a panel of NK-susceptible targets, including autologous B-LCLs. On the other hand, TAP2−/− NK cells were unable to kill either allogeneic (HLA class I+) or autologous (HLA class I− ) phytohemagglutinin (PHA) blasts even in the presence of anti-HLA class I monoclonal antibody. These data suggest that TAP2−/− NK cells express still unknown inhibitory receptor(s) capable of down-regulating the NK cell cytotoxicity on binding to surface ligand(s) expressed by T cell blasts. Functional analyses, both at the polyclonal and at the clonal level, are consistent with the concept that the putative inhibitory receptor is expressed by virtually all TAP2−/− NK cells, whereas it is present only in rare NK cells from healthy persons. Another possibility would be that TAP2−/− NK cells are missing a still unidentified triggering receptor involved in NK cell-mediated killing of PHA blasts.

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NK cell recognition of major histocompatibility complex class I molecules

Seminars in Immunology ◽

10.1006/smim.1995.0011 ◽

1995 ◽

Vol 7 (2) ◽

pp. 75-82 ◽

Cited By ~ 22

Author(s):

Lewis L. Lanier ◽

Joseph H. Phillips

Keyword(s):

Major Histocompatibility Complex ◽

Major Histocompatibility Complex Class ◽

Nk Cell ◽

Class I ◽

Cell Recognition ◽

Complex Class ◽

Major Histocompatibility ◽

Histocompatibility Complex ◽

Nk Cell Recognition

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HLA Class I Molecules as Immune Checkpoints for NK Cell Alloreactivity and Anti-Viral Immunity in Kidney Transplantation

Frontiers in Immunology ◽

10.3389/fimmu.2021.680480 ◽

2021 ◽

Vol 12 ◽

Author(s):

Burcu Duygu ◽

Timo I. Olieslagers ◽

Mathijs Groeneweg ◽

Christina E. M. Voorter ◽

Lotte Wieten

Keyword(s):

Kidney Transplantation ◽

Nk Cells ◽

Cell Activation ◽

Nk Cell ◽

Hla Class I ◽

Class I ◽

Immune Checkpoints ◽

Viral Immunity ◽

Nk Cell Receptors ◽

Hla Class I Molecules

Natural killer (NK) cells are innate lymphocytes that can kill diseased- or virally-infected cells, mediate antibody dependent cytotoxicity and produce type I immune-associated cytokines upon activation. NK cells also contribute to the allo-immune response upon kidney transplantation either by promoting allograft rejection through lysis of cells of the transplanted organ or by promoting alloreactive T cells. In addition, they protect against viral infections upon transplantation which may be especially relevant in patients receiving high dose immune suppression. NK cell activation is tightly regulated through the integrated balance of signaling via inhibitory- and activating receptors. HLA class I molecules are critical regulators of NK cell activation through the interaction with inhibitory- as well as activating NK cell receptors, hence, HLA molecules act as critical immune checkpoints for NK cells. In the current review, we evaluate how NK cell alloreactivity and anti-viral immunity are regulated by NK cell receptors belonging to the KIR family and interacting with classical HLA class I molecules, or by NKG2A/C and LILRB1/KIR2DL4 engaging non-classical HLA-E or -G. In addition, we provide an overview of the methods to determine genetic variation in these receptors and their HLA ligands.

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HLA upregulation during dengue virus infection suppresses the natural killer cell response

10.1101/698803 ◽

2019 ◽

Author(s):

Julia L. McKechnie ◽

Davis Beltran ◽

Arcelys Pitti ◽

Lisseth Saenz ◽

Ana B. Araúz ◽

...

Keyword(s):

Dengue Virus ◽

Nk Cells ◽

Natural Killer ◽

Cell Response ◽

Nk Cell ◽

Hla Class I ◽

Denv Infection ◽

Class I ◽

Hla Class I Molecules

AbstractDengue virus (DENV) is the most prevalent mosquito-borne virus in the world and a major cause of morbidity in the tropics and subtropics. Upregulation of HLA class I molecules has long been considered a feature of DENV infection, yet this has not been evaluated in the setting of natural infection. Natural killer (NK) cells, an innate immune cell subset critical for mounting an early response to viral infection, are inhibited by self HLA class I, suggesting that upregulation of HLA class I during DENV infection could dampen the NK cell response. Here we addressed whether upregulation of HLA class I molecules occurs during in vivo DENV infection and, if so, whether this suppresses the NK cell response. We found that HLA class I expression was indeed upregulated during acute DENV infection across multiple cell lineages in vivo. To better understand the role of HLA class I upregulation, we infected primary human monocytes, a major target of DENV infection, in vitro. Upregulation of total HLA class I is dependent on active viral replication and is mediated in part by cytokines and other soluble factors induced by infection, while upregulation of HLA-E occurs in the presence of replication-incompetent virus. Importantly, blocking DENV-infected monocytes with a pan-HLA class I Fab nearly doubles the frequency of degranulating NK cells, while blocking HLA-E does not significantly improve the NK cell response. These findings demonstrate that upregulation of HLA class I during DENV infection suppresses the NK cell response, potentially contributing to disease pathogenesis.

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