Review
The role of KIR positive NK cells in diseases and its importance in clinical intervention

https://doi.org/10.1016/j.intimp.2020.107361Get rights and content

Highlights

  • KIRs and specific KIR-HLA interaction could influence on the susceptibility/immunity of various diseases.

  • Suitable KIR-HLA combination in “in vitro fertilization” candidates may be helpful to increase the fertility rate.

  • NK cells participate in immune responses with the cytotoxicity, cytokine production, and regulatory activity on T lymphocytes and dendritic cells.

  • KIR+ NK cells could maintain the normal CD4+T cell counts in HIV patients.

Abstract

Natural killer (NK) cells are essential for the elimination of the transformed and cancerous cells. Killer cell immunoglobulin-like receptors (KIRs) which expressed by T and NK cells, are key regulator of NK cell function. The KIR and their ligands, MHC class I (HLA-A, B and C) molecules, are highly polymorphic and their related genes are located on 19 q13.4 and 6 q21.3 chromosomes, respectively. It is clear that particular interaction between the KIRs and their related ligands can influence on the prevalence, progression and outcome of several diseases, like complications of pregnancy, viral infection, autoimmune diseases, and hematological malignancies. The mechanisms of immune signaling in particular NK cells involvement in causing pathological conditions are not completely understood yet. Therefore, better understanding of the molecular mechanism of KIR-MHC class I interaction could facilitate the treatment strategy of diseases. The present review focused on the main characteristics and functional details of various KIR and their combination with related ligands in diseases and also highlights ongoing efforts to manipulate the key checkpoints in NK cell-based immunotherapy.

Introduction

Natural Killer (NK) cells were identified 30 years ago by the Kiesslling [1] and Herberman [2] as granular effector cells. NK cells can be recognized with CD56+CD3 phenotype [3]. Moreover, based on the expression level of the CD56, two subsets of NK cells: CD56bright and CD56dim have been introduced. CD56bright with cytokine production and imperfect cytotoxic activity only compose 10% of peripheral blood NK (pNK) cells, [4] whereas CD56dim with a totally mature feature like as short telomere lengths have high cytotoxic activity and represent around approximately 90% of pNK cells [5]. NK cells and cytotoxic T lymphocytes (CTL) are two complementary arms of the innate immune systems. Overall, the recognition and elimination of targets by NK cells occurs through the missing self-process by the balance between their activating and inhibitory receptors. In summary, the expression of MHC class I on tumor cells reduces or loses during tumoral transformation. In parallel, DNA damage can lead to the expression of activating ligands on the surface of transformed cells. Collectively, these changes are detected by NK cell receptors, and then they functionally eliminate unhealthy cells [6]. Among all NK cell receptors, killer cell immunoglobulin-like receptors (KIRs) expressed on memory T and NK cells [7] has important role in the education, development and function of NK cells. The genes of KIRs that encode both of the inhibitory and activating receptors are located on chromosome 19 q13.4 and show high diversity among the individuals and different populations [8]. As mentioned above, MHC class I (HLA-A, -B or -C) molecules on the healthy cell surface, are the specific ligands for KIRs. According to the KIRs and their ligands diversity, it is possible to predict the susceptibility or immunity to various diseases resulting from the various KIR-HLA combinations [9]. This review summarizes our existing knowledge on the NK cell receptors and their function. Albeit, our main focus is on the various KIR-HLA profiles in the different disease such as reproductive impairment, Human Immunodeficiency Virus (HIV), Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS) and hematological malignancies (Table 3). Finally, we tend to discuss the KIR-based strategies in cancer immunotherapy.

Section snippets

NK cell receptors, especially KIRs and their ligands

NK cells express various inhibitory and activating receptors responsible for their function. Natural cytotoxicity receptors (NCRs) including NKP46, NKP30, NKP44, KG2D, DNAM1 (also known as CD226), CD16 (Fc γ-RIIIa), C‐type lectin, UL16 (unique long 16), SLAM family, and some KIRs are known as the activating receptors [10], [11], [12], [13], [14], [15]. In addition, there are two main types of inhibitory receptors in human including KIRs and CD94-NKG2A. The KIRs are type I transmembrane

Inhibitory and activating KIRs signaling pathways

In general, activating and inhibitory KIRs signaling cascades are mediated by ITAM and ITIM-bearing transmembrane adaptor proteins, respectively. Following the inhibitory KIRs-MHC class I interaction, the tyrosine residue of ITIM becomes phosphorylated by Src family kinase [33], [34], [35]. The phosphorylated ITIM activates the recruitment of Src homology domain-containing tyrosine phosphatase (SHP-1, SHP-2) and SH2 domain-containing inositol-5-phosphatase (SHIP) [36]. Finally,

Association of KIR-HLA diversity with diseases

The involvement of KIR-HLA ligand combination in diseases has been clarified for decades. Due to the diversity of KIRs and HLA class I molecules, independent inheritance of these genes, and the various combination of different types of KIR receptors and HLA the susceptibility or immunity to some diseases could be vary in different individuals. Hence, in this review, influences of KIR-HLA interaction on reproduction, infection, autoimmune diseases, and AML are gathered in current review.

Therapeutic intervention based on the manipulation of the KIRs

Despite the pivotal role of NK cells in the elimination of abnormal cells [140], there is some evidence that the NK cells cytotoxic function is disrupted by the immune-suppressive microenvironment in the tumor sites [141]. In other word the tumor cells escape from killing by NK cells with the secretion of soluble factors and the shedding of activating ligands [142]. The tumor microenvironment specialty severely controls the NK cells function. For example the hypoxia in tumor microenvironment

Conclusion

The KIRs are the main regulators of immune tolerance, and their surface expression can significantly influence on the NK cell functions. The growing evidence indicates that KIRs and KIR-ligand polymorphisms have a main role in susceptibility or immunity to different diseases, including pregnancy complications, viral infection, and autoimmune diseases. The wide range of KIR-HLA combinations are important factors in pregnancy outcome. Therefore, HLA and KIR genotyping for IVF candidates may be

Declaration of Competing Interest

The author declares no conflict of interests.

Acknowledgements

The authors are especially grateful to the Stem Cell Research Center, Tabriz University of Medical Sciences for their support and assistance. This study was supported by the Stem Cell Research Center, Tabriz University of Medical sciences, Tabriz, Iran.

Funding

This work was supported by the Tabriz university of medical sciences [grant numbers 57895].

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