Abstract
KIR3DL2 is a member of the killer cell immunoglobulin-like receptor (KIR) family that was initially identified at the surface of natural killer (NK) cells. KIR3DL2, also known as CD158k, is expressed as a disulfide-linked homodimer. Each chain is composed of three immunoglobulin-like domains and a long cytoplasmic tail containing two immunoreceptor tyrosine-based inhibitory motifs. Beside its expression on NK cells, it is also found on rare circulating T lymphocytes, mainly CD8+. Although the KIR gene number varies between haplotype, KIR3DL2 is a framework gene present in all individuals. Together with the presence of genomic regulatory sequences unique to KIR3DL2, this suggests some particular functions for the derived protein in comparison with other KIR family members. Several ligands have been identified for KIR3DL2. As for other KIRs, binding to HLA class I molecules is essential for NK development by promoting phenomena such as licensing and driving NK cell maturation. For KIR3DL2, this includes binding to HLA-A3 and -A11 and to the free heavy chain form of HLA-B27. In addition, KIR3DL2 binds to CpG oligonucleotides (ODN) and ensures their transport to endosomal toll-like receptor 9 that promotes cell activation. These characteristics have implicated KIR3DL2 in several pathologies: ankylosing spondylitis and cutaneous T-cell lymphomas such as Sézary syndrome, CD30+ cutaneous lymphoma, and transformed mycosis fungoides. Consequently, a new generation of humanized monoclonal antibodies (mAbs) directed against KIR3DL2 has been helpful in the diagnosis, follow-up, and treatment of these diseases. In addition, preliminary clinical studies of a novel targeted immunotherapy for cutaneous T-cell lymphomas using the anti-KIR3DL2 mAb IPH4102 are now underway. In this review, we discuss the various aspects of KIR3DL2 on the functions of CD4+ T cells and how targeting this receptor helps to develop innovative therapeutic strategies.
Highlights
Introduction of monoclonal antibodies has been a very successful breakthrough for the diagnosis and treatment of a number of tumors
We focus on a class of such tumors, the cutaneous T-cell lymphomas (CTCL), which require improved identification of tumor markers and more efficient treatment
This study demonstrates that circulating CD3+CD4+KIR3DL2+ T-cell counts can be used to monitor treatment efficacy and relapse in Sézary syndrome (SS) patients
Summary
Introduction of monoclonal antibodies (mAbs) has been a very successful breakthrough for the diagnosis and treatment of a number of tumors. Rituximab (anti-CD20 mAb) was the first mAb approved for cancer therapy It has significantly improved patient survival in several B-cell malignancies such as diffuse large-cell lymphomas with response rate of 60–80% [1, 2]. FcR immune effectors [phagocytes and natural killer (NK) cells] play an essential role in the in vivo clearance of mAb-coated tumor cells [5,6,7,8] Another way of killing tumor cells by mAb is by F(ab′)2-dependent targeting of cell surface signaling receptors associated with apoptosis induction [9,10,11,12]. Sézary syndrome (SS) and mycosis fungoides (MF) are the most common forms of CTCL, both being very difficult to treat at advanced stages Their diagnosis is based on clinical, histopathological, molecular biological, and immunopathological features [14]. Promising targets include the C–C chemokine receptor type 4 (CCR4), CD30, programmeddeath 1, and KIR3DL2 to which therapeutic mAb has been designed and are currently in the clinical phase of study
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