CCR gene

The CCR8 gene (CCR8 stands for: C-C motif chemokine receptor 8) is a protein-coding gene located on chromosome 3p22.1. The CCR8 gene encodes a member of the beta-chemokine receptor family, which is thought to be a "seven transmembrane protein" similar to G protein-coupled receptors. An important paralog of this gene is CCR4.

Chemokine CC receptors (CCRs) predominantly recognize CC chemokines. CC chemokines are characterized by four conserved cysteines, with the first two cysteines adjacent to each other. There are 10 chemokine CC receptors (CCR1-10). The CCR8 receptor binds the ligands CCL1/SCYA1/I-309 and may regulate monocyte chemotaxis and thymic cell apoptosis. CCR8 serves as an alternative co-receptor with CD4 for HIV-1 infections.

Chemokines, a subgroup of cytokines, are small (size between 8 and 10 kDa), chemotactically active proteins (signaling proteins). They are found in all vertebrates, some virus species and bacteria. Around 50 chemokines are currently known in humans.

A strongly conserved structural feature of all chemokines is a fixed group of cysteine residues that is stabilized by 1 or 2 disulfide bridges. This key structural position in the molecule is responsible for their fixed 3-dimensional structure.

In the CC chemokines, the cysteines follow each other directly, in the CXC chemokines they are separated by 1 amino acid (CC = acronym for cysteine-cysteine), in the CXXXC chemokines by 3 other amino acids. Chemokines are produced and secreted by a large number of immune cells. They transmit their signals by binding to chemokine receptors via G proteins. Some chemokines have a pro-inflammatory effect, others have a regulatory effect on the development, homeostasis and proliferation of tissues.

The CCR6 receptor protein is preferentially expressed in the thymus. I-309, thymus activation-regulated cytokine (TARC) and macrophage inflammatory protein-1 beta (MIP-1 beta) have been identified as ligands of this receptor. Studies on this receptor and its ligands indicated its role in the regulation of monocyte chemotaxis and apoptosis of thymic cells. More specifically, this receptor may contribute to the correct positioning of activated T cells within antigenic target sites and specialized areas of lymphoid tissue. This gene is located in the chemokine receptor gene cluster region.

FOXP3+ regulatory T cells (Treg) play a critical role in mediating tolerance to self-antigens and can suppress antitumor immunity through various mechanisms. Therefore, targeted depletion of tumor-resident Tregs is required to promote effective antitumor immunity while maintaining peripheral homeostasis. Preclinical tumor models in mice showed that depletion of CCR8+ Tregs by an FcyR-binding anti-CCR8 antibody provided dose-dependent, potent and long-lasting antitumor immunity that acted synergistically with PD-1 blockade.These results suggest that anti-CCR8-nf antibodies may provide optimal tumor-targeted Treg depletion in the clinic, enabling long-term antitumor memory responses while limiting peripheral toxicities (Campbell JR et al. 2021).

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