The Role of Killer Ig-like Receptors in Diseases from A to Z

Abstract

Killer Ig-like Receptors (KIRs) regulate immune responses, maintaining the balance between activation and inhibition of the immune system. KIRs are expressed on natural killer cells and some CD8 T cells and interact with HLA class I molecules, influencing various physiological and pathological processes. KIRs' polymorphism creates a variability in immune responses among individuals. KIRs are involved in autoimmune disorders, cancer, infections, neurological diseases, and other diseases. Specific combinations of KIRs and HLA are linked to several diseases' susceptibility, progression, and outcomes. In particular, the balance between inhibitory and activating KIRs can determine how the immune system responds to pathogens and tumors. An imbalance can lead to an excessive response, contributing to autoimmune diseases, or an inadequate response, allowing immune evasion by pathogens or cancer cells. The increasing number of studies on KIRs highlights their essential role as diagnostic and prognostic biomarkers and potential therapeutic targets. This review provides a comprehensive overview of the role of KIRs in all clinical conditions and diseases, listed alphabetically, where they are analyzed.

Keywords: KIR; autoimmune diseases; genetic; polymorphisms.

Figure 1

Role of KIR genes in diseases: an alphabetical overview.

Figure 2

Biological functions of NK cells. NK cells recognize stressed cells (transformed or virus-infected cells) in the presence or absence of antibodies. Recognition ultimately leads to the elimination of the stressed cell and the production of cytokines by NK cells. NK cells can interact with DCs by killing immature DCs and promoting DC maturation through the release of IFN-γ and TNF-α, resulting in enhanced antigen presentation to T cells. Furthermore, NK cells modulate macrophage and T-cell responses by releasing IFN-γ and TNF-α, either potentiating or attenuating the respective immune reactions. NK: Natural killer cell; DC: Dendritic cell; IFN-γ: Interferon-γ; IL-10: Interleukin-10.

Figure 3

Characteristics and functions of NK-cell subpopulations: CD56bright and CD56dim. (a) CD56bright NK cells are characterized by high expression of CD56. They primarily secrete cytokines. (b) CD56dim NK cells, on the other hand, are characterized by lower expression of CD56 and higher expression of CD16. They primarily exert cytotoxic activity. ADCC: Antibody-dependent cellular cytotoxicity; LAK: lymphokine-activated killer cell.

Figure 4

The structure of KIR receptors. KIR receptors consist of three domains: extracellular, transmembrane, and intracellular. The extracellular domain has an Ig-like domain (D0–D2) and the receptor-binding area. The intracellular domain consists of a cytoplasmic tail. Inhibitory KIRs have long cytoplasmic tails with specific motifs (ITIMs). Activating KIRs have short cytoplasmic tails connected to adaptor proteins like DAP12 (ITAM). KIR2DL4 is the only exception, with a long cytoplasmic tail that signals both activation and inhibition.

Figure 5

Nomenclature of KIR receptors. (A) KIR2DS1, for example, has two extracellular domains (“2D”) and a short intracellular tail (“S”). (B) KIR3DL1 has three extracellular domains (“3D”) and a long intracellular tail (“L”).

Figure 6

Haplotypes A and B of KIR genes. The KIR gene cluster is located on chromosome 19q13.4. Human NK cells express various combinations of these 17 genes with two common haplotypes: haplotype A and haplotype B. This model identifies the centromeric region, anchored by the framework genes KIR3DL3 and KIR3DP1. Moving towards the telomeric end from KIR3DP1, the framework gene KIR2DL4 marks the telomeric portion, subsequently bounded by the concluding framework gene KIR3DL2.

Figure 7

NK-cells activity. It is regulated by a balance of signals from activating and inhibitory receptors: (A) In the absence of interaction between the activating receptor and its ligand on the target cell, lysis is inhibited when inhibitory receptors bind to cognate class I MHC molecules on the surface of the target cell or the normal cell (self). (B) A predominance of inhibitory receptor–inhibitor interactions with class I MHC results in a net negative signal that prevents NK-cell lysis. (C) Activating receptor interactions with ligands on the target cell predominate over weaker MCH class I ligand inhibitory receptor signal, with the net result of NK-cell activation and target cell lysis. This can occur when activating receptors and/or ligands are upregulated, thereby amplifying the net activating signal to overcome the inhibitory signal. (D) Lysis occurs when the activating receptor engages its ligand on the target cell in the absence of interactions with the inhibitory receptor and the MHC class I molecule. MCH: Major Histocompatibility Complex; KIR: Killer immunoglobulin-like receptor.

Figure 8

The interaction of KIR with HLA ligands. (A), inhibitory receptors. (B), activatory receptors.

Figure 9

Systemic and organ-specific autoimmune diseases: classification based on autoantibody localization.