KIR2DL3

KIR2DL3 Full Name

killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3

KIR2DL3 Introduction

Killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1), also designated as CD158a, is an inhibitory receptor belonging to the killer cell immunoglobulin-like receptor (KIR) family. Encoded by the KIR2DL1 gene within the leukocyte receptor complex on chromosome 19q13.4, KIR2DL1 is primarily expressed on the surface of natural killer (NK) cells and subsets of CD8+ and γδ T cells. As an inhibitory KIR, KIR2DL1 recognizes specific human leukocyte antigen (HLA) class I molecules — primarily HLA-C allotypes carrying the Lys80 epitope (group 2 HLA-C, e.g., HLA-Cw2, -Cw4, -Cw5, -Cw6) — and upon ligand engagement, delivers an inhibitory signal that suppresses NK cell cytotoxicity and cytokine secretion.

Figure 1. Strcuture of KIR2DL3.

Inhibitory Signaling and NK Cell Education
KIR2DL1 contains two extracellular immunoglobulin-like domains (D1 and D2) that mediate HLA-C recognition, a transmembrane region, and a long cytoplasmic tail harboring two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Ligand binding induces KIR2DL1 clustering and tyrosine phosphorylation of its ITIMs, predominantly by Src-family kinases. Phosphorylated ITIMs recruit the SH2 domain-containing protein tyrosine phosphatases SHP-1 and SHP-2, which dephosphorylate key signaling intermediates including Vav1, PLCγ, and LAT downstream of activating NK cell receptors (e.g., NKG2D, CD16, activating KIRs). This dephosphorylation cascade prevents the assembly of productive activating signaling complexes, effectively raising the threshold for NK cell activation. This inhibitory mechanism is essential for NK cell self-tolerance — during NK cell development, engagement of inhibitory KIRs by self-HLA class I molecules educates (licenses) NK cells, rendering them functionally competent to respond to targets that have lost HLA class I expression (missing-self recognition).

KIR2DL1-HLA Interactions in Transplantation, Infection, and Reproduction
The interaction between KIR2DL1 and its cognate HLA-C ligands has profound clinical implications. In hematopoietic stem cell transplantation (HSCT), donor NK cells expressing KIR2DL1 that are mismatched with recipient HLA-C ligands can mediate potent graft-versus-leukemia (GvL) effects through missing-self recognition of leukemic blasts, reducing relapse rates without increasing graft-versus-host disease in certain transplantation protocols. In viral infections, particularly HIV and hepatitis C virus (HCV), specific combinations of KIR2DL1 and HLA-C genotypes have been associated with differential rates of disease progression and viral clearance, reflecting the importance of NK cell-mediated control of viral replication. In reproduction, KIR2DL1 expressed by uterine NK cells (uNK) interacts with HLA-C on fetal trophoblast cells at the maternal-fetal interface; certain KIR/HLA-C combinations are associated with an increased risk of pregnancy complications including pre-eclampsia and recurrent miscarriage. KIR genotyping is increasingly incorporated into donor selection algorithms for haploidentical HSCT and is being evaluated as a prognostic marker in reproductive medicine.

Alternate Names for KIR2DL3

KIR2DL3; killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3; p58; NKAT; GL183; NKAT2; CD158b; NKAT2A; NKAT2B; CD158B2

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