CCR4 gene

CCR4 (C-C Motif Chemokine Receptor 4) is a protein-coding gene located on chromosome 3p22.3 that encodes the eponymous, CCR4 receptor. CCR4 receptor protein belongs to the G protein-coupled transmembrane chemokine receptor family. CCR4 a high-affinity receptor for the C-C chemokines CCL3 (MIP-1), CCL4 (RANTES), CCL17 (TARC), and MCP-1, CCR4 protein activity is mediated by G(i) proteins that activate a phosphatidylinositol calcium second messenger system. The receptor may function as a chemoattractive homing receptor on circulating memory lymphocytes and as a co-receptor for some primary HIV-2 isolates. In the CNS, it appears to be important for the survival of hippocampal neurons.

Chemokine CC receptors (CCRs) predominantly recognize CC chemokines (Yoshie O et al. 2015). Chemokines are a group of small, structurally related polypeptide molecules that regulate cell trafficking of various types of leukocytes. Chemokines also play a fundamental role in the development, homeostasis, and function of the immune system and have effects on cells of the central nervous system as well as endothelial cells involved in angiogenesis.An important paralog of this gene is CCR5.

CC chemokines are characterized by having four conserved cysteines. In CC chemokines the cysteines follow each other directly, in CXC chemokines they are separated (CC = acronym for cysteine-cysteine) by 1, in CXXXC chemokines by 3 other amino acids.

Chemokines are produced and secreted by a variety of immune cells, but also by parenchymal cells (e.g. hepatocytes, myocytes). Some chemokines have a proinflammatory effect, others have a regulatory effect in the formation and homeostasis of tissues.

Among the various T cell subsets, CCR4 is mainly expressed by Th2 cells, cutaneous lymphocyte antigen-positive T cells, and Treg cells. In addition, CCR4 is frequently expressed by mature T cell neoplasms such as adult T cell leukemia/lymphoma(ATL) and cutaneous T cell lymphoma (CTCL) (Ferenczi K et al. 2002; Yoshie O et al. 2015). This expression pattern opened up possibilities for clinical application in diseases involving these T cell subsets (Ishida T et al. 2006).

The humanized defucosylated anti-CCR4 antibody"Mogamulizumab" has been successfully used for the treatment of relapsed/refractory ATL and CTCL (Mogamulizumab has been approved since 2018).

1. Ferenczi K et al (2002) Increased CCR4 expression in cutaneous T cell lymphoma. J Invest Dermatol 119:1405-1410.
2. Ishida Tet al (2006) CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci 97:1139-1146.
3. Shimauchi T et al (2005) Production of thymus and activation-regulated chemokine and macrophage-derived chemokine by CCR4+ adult T-cell leukemia cells. Clin Cancer Res 11:2427-2435.
4. Yoshie O et al (2015) CCR4 and its ligands: from bench to bedside. Int Immunol 27:11-20.