Surface NK receptors and their ligands on tumor cells

doi:10.1016/j.smim.2006.03.002

Seminars in Immunology

Volume 18, Issue 3, June 2006, Pages 151-158

https://doi.org/10.1016/j.smim.2006.03.002 Get rights and content

Abstract

The identification of MHC-class I-specific inhibitory receptors in humans and mice provided a first explanation of why NK cells can kill target cells that have lost or underexpress MHC-class I molecules but spare normal cells. However, the molecular basis of NK-mediated recognition and tumor cell killing revealed a higher degree of complexity. Thus, under pathological conditions, NK cells may express insufficient amounts of triggering receptors and target cells may or may not express ligands for such receptors. Here we briefly illustrate the main NK receptors and their cellular ligands and we delineate the major receptor/ligands interactions leading to NK cell activation and tumor cell lysis.

Introduction

For many years after their discovery natural killer (NK) cells have been defined using rather imprecise phenotypic and functional criteria. They were originally identified on a functional basis, i.e. the capability of killing certain tumor cell lines in the absence of a deliberate previous stimulation [1]. Different from T or B lymphocytes, NK cells do not express clonally-distributed receptors for antigen. They are characterized by a strong cytolytic activity against tumor or virus-infected cells as well as by the ability to release cytokines and chemokines that mediate inflammatory responses and exert a regulatory effect on the adaptive immune responses [2], [3]. Major questions regarding the molecular mechanisms by which NK cells function has long remained unanswered. However, this has dramatically changed in recent years and we now have a fairly accurate understanding of the general mechanisms that regulate NK cell function and allow them to spare normal cells and kill tumor or virus-infected cells [4], [5]. A key role was played by the identification of various receptors responsible for the process of NK cell activation or inactivation [5], [6], [7]. In this review we will briefly illustrate the surface NK receptors and their specific ligands (identified so far) that contribute to the NK-mediated immune responses.

Section snippets

Role of HLA-class I-specific inhibitory NK receptors and of HLA-class I molecules in the process of NK cell inactivation

Parallel studies in humans [8], [9], [10] and mice [11] revealed that NK cells recognize MHC-class I molecules via surface receptors delivering signals that inhibit, rather than activate, NK cell cytolytic function. When these inhibitory receptors (iNKR) are not engaged by MHC-class I molecules on target cells, this can lead to NK cell activation and target cell killing [12], [13]. This situation may occur when target cells have lost or express insufficient amounts of MHC-class I molecules, a

HLA-class I-specific inhibitory NK receptors

The CD94/NKG2A receptor recognizes the poorly polymorphic (class Ib) HLA-E molecule [19]. HLA-E surface expression is dependent on the availability of peptides derived from the leader sequence of various HLA-class I alleles. Accordingly, the HLA-E surface expression correlates with the overall expression of HLA-class I molecules on cells [20].

KIR, encoded by a diverse and rapidly evolving family of genes, recognize allelic determinants of HLA-class I molecules [21], [22] (Table 1). The

Expression of HLA-class I molecules on target cells

It is noteworthy that the failure to express one or more HLA-class I alleles can represent a major threat to host integrity. In this context, certain cytopathic viruses (e.g. herpes viruses and adenoviruses) have developed strategies to escape the control exerted by CTL [16], [17]. For example, CMV codes for different “unique short” (US) proteins that block the surface expression of HLA-class I molecules in infected cells [16], [31], [32]. This explains why NK cells (and HLA-E-restricted CTLs)

Effect of KIR-HLA-class I mismatch in an allogeneic setting: the example of haploidentical BM transplantation

While NK cells fail to attack normal cells in an autologous setting, they may kill allogeneic cells. “Alloreactive” NK cells were described by our group in late’ 80 [44]. Subsequently, it became evident that alloreactivity is due to mismatches between KIR expressed by NK cells and HLA-class I molecules expressed by allogeneic cells [9], [12], [18], [45], [46]. A paradigmatic example is represented by the haploidentical BM transplantation in which only one of the HLA-carrying chromosomes is

Activating NK receptors and their cellular ligands

Having established that NK cell inactivation elicited by the interaction between iNKR and HLA-class I molecules represents a major fail-safe mechanism to prevent NK-mediated attack to normal HLA-class I⁺ cells, it is evident that an activating signal must be generated when NK cells interact with potential target cells. This activation signal can be readily detected when target cells lack HLA-class I molecules [4]. The NK receptors responsible for NK cell activation in the process of natural

Natural cytotoxicity receptors and their still elusive cellular ligands

NKp46 [53], [54] and NKp30 [55] are present on both resting and activated NK cells, while NKp44 [56], [57] is expressed upon NK cell activation. They represent highly specific NK cell markers as well as the most important receptors in the NK cell-mediated tumor cell lysis [55], [58] (Fig. 1). Their surface density has been shown to correlate with the magnitude of the NK cytolytic activity against susceptible targets. NCR associate with different transmembrane-anchored polypeptides bearing

NKG2D receptor and its cellular ligands MICA/B and ULBPs

NKG2D is a homodimeric receptor expressed by NK cells and by a fraction of T lymphocytes [78] (Fig. 1). It is characterized by a lectin-like domain and, in spite of its denomination it is only distantly related to the inhibitory receptor NKG2A and does not associate with CD94. NKG2D specifically binds to stress-inducible, MHC-like molecules containing an α-domain with MHC-class I folds express at the cell surface without association with β2-microglobulin and peptide [79], [80]. These ligands

The DNAM-1 receptor and its ligands: the poliovirus receptor and nectin-2

A cell surface molecule capable of enhancing cytolytic activity and cytokine production in both T [89] and NK cells was named DNAX accessory molecule-1 (DNAM-1, CD226) [90]. More recently, Bottino et al. could identify its ligands represented by two members of the nectin family: the poliovirus receptor (PVR CD155) and nectin-2 (CD112) [64]. Both molecules can be highly expressed in tumor cell lines, including carcinomas, melanomas and neuroblastomas. In agreement with these data, the role of

Cell surface ligands for unknown receptors

While NCR represent orphan receptors, recent experimental evidence revealed a ligand for which the existence of a specific receptor has not been identified so far and can only be postulated. This molecule, termed “four Ig-like B7-homologue 3 (4Ig-B7-H3) [93], [94], belongs to the B7 family that encompasses a series of Ig-like molecules typically expressed by antigen-presenting cells. In addition to CD80 and CD86, the B7 family includes a series of B7-homologues (B7-H) [95], [96]. Some of these

Concluding remarks

It is evident that major progresses have been made during the past 15 years in the understanding of the molecular mechanisms involved in NK cell function. Thus, numerous receptors with opposing functions and many of their ligands have been identified and molecularly characterized. However, there are still relevant issues that remain to be clarified in order to better understand the NK cell physiology and possibly to exploit them in immunotherapy. For example, it will be important to identify

Acknowledgments

This work was supported by grants awarded by Associazione Italiana per la Ricerca sul Cancro (AIRC), Istituto Superiore di Sanità (ISS), Ministero della Salute, RF 2002/149, Ministero dell’Istruzione dell’Università e della Ricerca (MIUR), FIRB-MIUR progetto, cod.RBNE017B4C; Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST), European Union FP6, LSHB-CT-2004-503319-Allostem (The European Commission is not liable for any use that may be made of the information

References (99)

G. Trinchieri
Biology of natural killer cells
Adv Immunol
(1989)
A. Moretta
The dialogue between human natural killer cells and dendritic cells
Curr Opin Immunol
(2005)
C. Bottino et al.
Cellular ligands of activating NK receptors
Trends Immunol
(2005)
H.G. Ljunggren et al.
In search of the “missing self”. MHC molecules and NK cell recognition
Immunol Today
(1990)
A. Alcami et al.
Viral mechanisms of immune evasion
Immunol Today
(2000)
S. Rajagopalan et al.
Viral evasion of NK-cell activation
Trends Immunol
(2005)
J. Trowsdale
Genetic and functional relationships between MHC and NK receptor genes
Immunity
(2001)
A. Zingoni et al.
Lanier LL NK cell regulation of T cell-mediated responses
Mol Immunol
(2005)
M.C. Mingari et al.
Regulation of KIR expression in human T lymphocytes. A safety mechanism which may impair protective T cell responses
Immunol Today
(1998)
L. Moretta et al.
NK-CTL, a novel HLA-E-restricted T cell subset
Trends Immunol
(2003)

L. Moretta et al.

Different checkpoints in human NK-cell activation

Trends Immunol

(2004)

L. Moretta et al.

Killer immunoglobulin-like receptors

Curr Opin Immunol

(2004)

A. Velardi et al.

NK cells: a lesson from mismatched hematopoietic transplantation

Trends Immunol

(2002)

D. Pende et al.

Analysis of the receptor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the poliovirus receptor (CD155) and nectin-2 (CD112)

Blood

(2005)

L. Ruggeri et al.

Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation

Blood

(1999)

A. Moretta et al.

Natural cytotoxicity receptors that trigger human NK-cell-mediated cytolysis

Immunol Today

(2000)

C. Bottino et al.

Learning how to discriminate between friends and enemies, a lesson from natural killer cells

Mol Immunol

(2004)

S. Sivori et al.

Involvement of natural cytotoxicity receptors in human natural killer cell-mediated lysis of neuroblastoma and glioblastoma cell lines

J Neuroimmunol

(2000)

R.T. Costello et al.

Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia

Blood

(2002)

E. Carbone et al.

HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells

Blood

(2005)

M. Falco et al.

Identification of the rat homologue of the human NKp46 triggering receptor

Immunol Lett

(1999)

T.I. Arnon et al.

The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46

Blood

(2004)

D. Cosman et al.

ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor

Immunity

(2001)

L. Raffaghello et al.

Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma

Neoplasia

(2004)

A. Shibuya et al.

DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes

Immunity

(1996)

C.A. Biron et al.

Natural killer cells in antiviral defense: function and regulation by innate cytokines

Annu Rev Immunol

(1999)

A. Moretta et al.

Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis

Annu Rev Immunol

(2001)

L.L. Lanier

NK cell recognition

Annu Rev Immunol

(2005)

P. Parham

MHC class I molecules and KIRs in human history, health and survival

Nat Rev Immunol

(2005)

A. Moretta et al.

A novel surface antigen expressed by a subset of human CD3-CD16+ natural Killer cells. Role in cell activation and regulation of cytolytic function

J Exp Med

(1990)

A. Moretta et al.

Identification of four subsets of human CD3-CD16+ NK cells by the expression of clonally distributed functional surface molecules. Correlation between subset assignment of NK clones and ability to mediate specific alloantigen recognition

J Exp Med

(1990)

A. Moretta et al.

p58 molecules as putative receptors for MHC class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities

J Exp Med

(1993)

W.M. Yokoyama et al.

The ly49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex

Annu Rev Immunol

(1993)

A. Moretta et al.

Receptors for HLA-class I molecules in human natural killer cells

Annu Rev Immunol

(1996)

F. Garrido et al.

Implications for immunosurveillance of altered HLA-class I phenotypes in human tumours

Immunol Today

(1997)

I. Algarra et al.

The selection of tumor variants with altered expression of classical and nonclassical MHC class I molecules: implications for tumor immune escape

Cancer Immunol Immunother

(2004)

E.O. Long

Regulation of immune responses through inhibitory receptors

Annu Rev Immunol

(1999)

V.M. Braud et al.

HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C

Nature

(1998)

E.O. Long

Signal sequences stop killer cells

Nature

(1998)

C. Vilches et al.

KIR: diverse, rapidly evolving receptors of innate and adaptive immunity

Annu Rev Immunol

(2002)

H.G. Shilling et al.

Genetic control of human NK cell repertoire

J Immunol

(2002)

M.C. Mingari et al.

T lymphocytes displaying natural killer (NK)-like activity: expression of NK-related functional receptors for HLA class I molecules (p58 and CD94) and inhibitory effect on the TCR-mediated target cell lysis or lymphokine production

Int Immunol

(1995)

M.C. Mingari et al.

Human CD8+ T lymphocyte subsets that express HLA-class I specific inhibitory receptors represent oligoclonally or monoclonally expanded cell populations

Proc Natl Acad Sci (USA)

(1996)

G. Pietra et al.

The analysis of the Natural Killer-like activity of human cytolytic T lymphocytes revealed HLA-E as a novel target for TCR-mediated recognition

Eur J Immunol

(2001)

G. Pietra et al.

HLA-E-restricted recognition of cytomegalovirus-derived peptides by human CD8+ cytolytic T lymphocytes

Proc Natl Acad Sci (USA)

(2003)

M. Lopez-Botet et al.

Natural killer cell receptors for major histocompatibility complex class I and related molecules in cytomegalovirus infection

Tissue Antigens

(2004)

M.B. Lodoen et al.

Viral modulation of NK cell immunity

Nat Rev Microbiol

(2005)

M.S. Malnati et al.

Peptide specificity in the recognition of MHC class I by natural killer cell clones

Science

(1995)

S. Sivori et al.

CpG and dsRNA trigger human NK cells via TLR. Induction of cytokine release and of cytolytic activity against tumors and immature DC

Proc Natl Acad Sci USA

(2004)

Cited by (238)

NK cell tumor therapy modulated by UV-inactivated oncolytic herpes simplex virus type 2 and checkpoint inhibitors
2022, Translational Research
Oncolytic virotherapy is a new and safe therapeutic strategy for cancer treatment. In our previous study, a new type of oncolytic herpes simplex virus type 2 (oHSV2) was constructed. Following the completion of a preclinical study, oHSV2 has now entered into clinical trials for the treatment of melanoma and other solid tumors (NCT03866525). Oncolytic viruses (OVs) are generally able to directly destroy tumor cells and stimulate the immune system to fight tumors. Natural killer (NK) cells are important components of the innate immune system and critical players against tumor cells. But the detailed interactions between oncolytic viruses and NK cells and these interaction effects on the antitumor immune response remain to be elucidated. In particular, the functions of activating surface receptors and checkpoint inhibitors on oHSV2-treated NK cells and tumor cells are still unknown. In this study, we found that UV-oHSV2 potently activates human peripheral blood mononuclear cells, leading to increased antitumor activity in vitro and in vivo. Further investigation indicated that UV-oHSV2-stimulated NK cells release IFN-γ via Toll-like receptor 2 (TLR2)/NF-κB signaling pathway and exert antitumor activity via TLR2. We found for the first time that the expression of a pair of checkpoint molecules, NKG2A (on NK cells) and HLA-E (on tumor cells), is upregulated by UV-oHSV2 stimulation. Anti-NKG2A and anti-HLA-E treatment could further enhance the antitumor effects of UV-oHSV2-stimulated NK92 cells in vitro and in vivo. As our oHSV2 clinical trial is ongoing, we expect that the combination therapy of oncolytic virus oHSV2 and anti-NKG2A/anti-HLA-E antibodies may have synergistic antitumor effects in our future clinical trials.
Natural killer cell-based strategies for immunotherapy of cancer
2022, Advances in Protein Chemistry and Structural Biology
Natural killer (NK) cells are a family of lymphocytes with a natural ability to kill infected, harmed, or malignantly transformed cells. As these cells are part of the innate immunity, the cytotoxic mechanisms are activated upon recognizing specific patterns without prior antigen sensitization. This recognition is crucial for NK cell function in the maintenance of homeostasis and immunosurveillance. NK cells not only act directly toward malignant cells but also participate in the complex immune response by producing cytokines or cross-talk with other immune cells. Cancer may be seen as a break of all immune defenses when malignant cells escape the immunity and invade surrounding tissues creating a microenvironment supporting tumor progression. This process may be reverted by intervening immune response with immunotherapy, which may restore immune recognition. NK cells are important effector cells for immunotherapy. They may be used for adoptive cell transfer, genetically modified with chimeric antigen receptors, or triggered with appropriate antibodies and other antibody-fragment-based recombinant therapeutic proteins tailored specifically for NK cell engagement. NK cell receptors, responsible for target recognition and activation of cytotoxic response, could also be targeted in immunotherapy, for example, by various bi-, tri-, or multi-specific fusion proteins designed to bridge the gap between tumor markers present on target cells and activation receptors expressed on NK cells. However, this kind of immunoactive therapeutics may be developed only with a deep functional and structural knowledge of NK cell receptor: ligand interactions. This review describes the recent developments in the fascinating protein-engineering field of NK cell immunotherapeutics.
The promise of bispecific antibodies: Clinical applications and challenges
2021, Cancer Treatment Reviews
The development of cancer therapies using monoclonal antibodies has been successful during the last 30 years. Recently much progress was achieved with technologies involving bispecific and multi-specific antibodies. Bispecific antibodies (BsAbs) are antibodies that bind two distinct epitopes, and a large number of potential clinical applications of BsAbs have been described. Here we review mechanism of action, clinical development and future challenges of BsAbs which could be a serve as a valuable arsenal in cancer patients.
Inhibitory axes impacting on the activity and fate of Innate Lymphoid Cells
2021, Molecular Aspects of Medicine
In neoplastic patients, an effective immune response ideally should be achieved by the coordinated action of different immune cells with tumor-suppressive functions. These include the more cytolytic members of the Innate Lymphoid Cells (ILCs) family represented by the Natural Killer (NK) cells, whose activities in cancer patients, however, can be hampered by several inhibitory signals. These are generated by membrane-bound and soluble molecules that, interacting with specific inhibitory receptors, create inhibitory axes impacting the NK cell differentiation and effector functions. These breaks, which now represent major immunotherapeutic targets, may be sensitive to interferon (IFN)-γ, whose source, in vivo, is represented by different cell types including the NK and ILC1. Since also ILCs can express receptors of the inhibitory axes like PD-1 and TIGIT, their therapeutic blockade might further amplify the IFN-γ release that, as an unwanted side effect, would promote the onset of NK cell-resistant tumor variants (NKRTV) expressing ligands involved in inhibitory axes. These variants might also arise from the activity of other cytokines such as IL-27, which can increase the expression of HLA class I and PD-Ls in different cell types, including tumor cells. Besides the amplification of membrane-bound inhibitory axes, tumors can reduce the number of infiltrating cytolytic ILCs, promote the recruitment of poorly cytolytic NK cell subsets, and manipulate to their advantage the infiltrating immune cells, which acquire tumor-promoting activities. This occurs thanks to the production of soluble factors including TGF-β1 and IL-18 that, alone or in combination, modify the activating and chemokine receptor repertoire of NK cells, and induce the ILCs differentiation towards cells ineffective in fighting cancer or, even worse, with tumor-promoting functions.
The present review aims to present and discuss major inhibitory axes impacting on ILCs functions, migration, and differentiation with a major focus on tumor context.
The effects of stereotactic body radiotherapy on peripheral natural killer and CD3<sup>+</sup>CD56<sup>+</sup> NKT-like cells in patients with hepatocellular carcinoma
2021, Hepatobiliary and Pancreatic Diseases International
Both natural killer (NK) and CD3⁺CD56⁺natural killer T (NKT)-like cells play critical roles in the antitumor response. This study aimed to explore the effects of stereotactic body radiotherapy (SBRT) on peripheral NK and NKT-like cells in patients with hepatocellular carcinoma (HCC), and to identify possible surface markers on these cells that correlate with the prognosis.
Twenty-five HCC patients were prospectively enrolled in our study, and 10 healthy individuals were served as healthy controls. Flow cytometry was used to determine the counts and the percentages of peripheral NK and NKT-like cells, cells with certain receptors, and cells with intracellular interferon-γ and TNF-α secretion at different time points, including time points of prior to SBRT, at post-SBRT, and 3-month and 6-month after treatment. The Kaplan-Meier method with the log-rank test was applied for survival analysis.
The peripheral NKT-like cells was increased at post-SBRT. Meanwhile, elevated levels of inhibitory receptors and reduced levels of activating receptors of NK cells were also observed in NK cells at post-SBRT, but the levels was not significantly different at 3-month and 6-month as compared with the baseline levels. Lower percentage of NKp30⁺NK cells before SBRT and higher percentage of CD158b⁺NK cells after SBRT were associated with poor progression-free survival. In addition, higher percentage of CD3⁺CD56⁺ NKT-like cells was associated with a higher overall survival rate in HCC patients.
SBRT has an apparent effect on both peripheral NK and CD3⁺CD56⁺NKT-like cells. Lower percentage of NKp30⁺NK cells before SBRT and higher percentage of CD158b⁺NK cells after SBRT are correlated with poor patients' PFS. Higher percentage of CD3⁺CD56⁺ NKT-like cells is associated with higher OS in HCC patients.
Selective downregulation of natural killer activating receptors on NK cells and upregulation of PD-1 expression on T cells in children with severe and/or recurrent Herpes simplex virus infections
2021, Immunobiology
Severe, recurrent or atypical Herpes simplex virus (HSV) infections are still posing clinical and diagnostic problem in clinical immunology facilities. However, the molecular background of this disorder is still unclear. The aim of this study was to investigate the expression of activating receptors on NK cells (CD16, NKp46, NKG2D, NKp80, 2B4, CD48 and NTB-A) and checkpoint molecule PD-1 on T lymphocytes and NK cells, in patients with severe and/or recurrent infections with HSV and age-matched healthy control subjects. As a result, we noticed that patients with severe and/or recurrent infection with HSV had significantly lower percentage of CD16^brightCD56^dim and higher percentage of CD16^dimCD56^bright NK cell subsets, when compared to control subjects, which may be associated with abnormal NK cell maturation during chronic HSV infection. Patients had also significantly downregulated expression of CD16 receptor on CD16^bright NK cells. The expression of activating receptors was significantly reduced on patients’ NK cells - either both the percentage of NK cells expressing the receptor and MFI of its expression (NKp46, NKp80 and 2B4 on CD16^brightCD56^dim cells and NKp46 on CD16^dimCD56^bright cells) or only MFI (NKG2D on both NK cell subsets). It should be noted that the reduction of receptor expression was limited to NK cells, since there was no differences in the percentage of receptor-positive cells or MFI on T cells. However, NTB-A receptor was the only one which expression was not only simultaneously changed in patients’ NK and T cells, but also significantly upregulated on CD16^dimCD56^bright NK cell and CD8⁺ cell subsets. Patients had also upregulated proportion of CD4⁺ T cells expressing PD-1. Thus, we suggest that an increased percentage of PD-1⁺ cells may represent an independent indirect mechanism of downregulation of antiviral response, separate from the reduction of NK cell activating receptors expression. Altogether, our studies indicate two possible mechanisms which may promote perpetuation of HSV infection: 1) selective inhibition of activating receptors on NK cells, but not on T cells, and 2) upregulation of checkpoint molecule PD-1 on CD4⁺ T cells.

View all citing articles on Scopus

View full text

ReviewSurface NK receptors and their ligands on tumor cells

Abstract

Introduction

Section snippets

Role of HLA-class I-specific inhibitory NK receptors and of HLA-class I molecules in the process of NK cell inactivation

HLA-class I-specific inhibitory NK receptors

Expression of HLA-class I molecules on target cells

Effect of KIR-HLA-class I mismatch in an allogeneic setting: the example of haploidentical BM transplantation

Activating NK receptors and their cellular ligands

Natural cytotoxicity receptors and their still elusive cellular ligands

NKG2D receptor and its cellular ligands MICA/B and ULBPs

The DNAM-1 receptor and its ligands: the poliovirus receptor and nectin-2

Cell surface ligands for unknown receptors

Concluding remarks

Acknowledgments

Adv Immunol

Curr Opin Immunol

Trends Immunol

Immunol Today

Immunol Today

Trends Immunol

Immunity

Mol Immunol

Immunol Today

Trends Immunol

Trends Immunol

Curr Opin Immunol

Trends Immunol

Blood

Blood

Immunol Today

Mol Immunol

J Neuroimmunol

Blood

Blood

Immunol Lett

Blood

Immunity

Neoplasia

Immunity

Natural killer cells in antiviral defense: function and regulation by innate cytokines

Annu Rev Immunol

Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis

Annu Rev Immunol

NK cell recognition

Annu Rev Immunol

MHC class I molecules and KIRs in human history, health and survival

Nat Rev Immunol

A novel surface antigen expressed by a subset of human CD3-CD16+ natural Killer cells. Role in cell activation and regulation of cytolytic function

J Exp Med

Identification of four subsets of human CD3-CD16+ NK cells by the expression of clonally distributed functional surface molecules. Correlation between subset assignment of NK clones and ability to mediate specific alloantigen recognition

J Exp Med

p58 molecules as putative receptors for MHC class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities

J Exp Med

The ly49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex

Annu Rev Immunol

Receptors for HLA-class I molecules in human natural killer cells

Annu Rev Immunol

Implications for immunosurveillance of altered HLA-class I phenotypes in human tumours

Immunol Today

The selection of tumor variants with altered expression of classical and nonclassical MHC class I molecules: implications for tumor immune escape

Cancer Immunol Immunother

Regulation of immune responses through inhibitory receptors

Annu Rev Immunol

HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C

Nature

Signal sequences stop killer cells

Nature

KIR: diverse, rapidly evolving receptors of innate and adaptive immunity

Annu Rev Immunol

Genetic control of human NK cell repertoire

J Immunol

T lymphocytes displaying natural killer (NK)-like activity: expression of NK-related functional receptors for HLA class I molecules (p58 and CD94) and inhibitory effect on the TCR-mediated target cell lysis or lymphokine production

Int Immunol

Human CD8+ T lymphocyte subsets that express HLA-class I specific inhibitory receptors represent oligoclonally or monoclonally expanded cell populations

Proc Natl Acad Sci (USA)

The analysis of the Natural Killer-like activity of human cytolytic T lymphocytes revealed HLA-E as a novel target for TCR-mediated recognition

Eur J Immunol

HLA-E-restricted recognition of cytomegalovirus-derived peptides by human CD8+ cytolytic T lymphocytes

Proc Natl Acad Sci (USA)

Review
Surface NK receptors and their ligands on tumor cells