CCL5
Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the "CCL5" gene. The gene has been discovered in 1990 by "in situ" hybridisation and it is localised on 17q11.2-q12 chromosome. It is also known as RANTES (regulated on activation, normal T cell expressed and secreted). RANTES was first described by Dr. Tom Schall who named the protein, the original source of the name Rantes was from the Argentine movie "Man Facing Southeast" about an alien who shows up in a mental ward who was named Rantés, the rather clunky acronym  was only made to fit the name. Function. CCL5 belongs to the CC subfamily of chemokines, due to its adjacent cysteines near N terminus. It is an 8kDa protein acting as a classical chemotactic cytokine or chemokine. It consists of 68 amino acids. CCL5 is proinflammatory chemokine, recruiting leukocytes to the site of inflammation. It is chemotactic for T cells, eosinophils, and basophils, but also for monocytes, natural-killer (NK) cells, dendritic cells and mastocytes. With the help of particular cytokines (i.e., IL-2 and IFN-γ) that are released by T cells, CCL5 also induces the proliferation and activation of  certain NK cells to form CHAK (CC-Chemokine-activated killer) cells. It is also an HIV-suppressive factor released from CD8+ T cells The chemokine CCL5 is mainly expressed by T-cells and monocytes, and it has not been shown to be expressed by B-cells. Moreover, it is abundantly expressed by epithelial cells, fibroblasts and thrombocytes. Although it can bind to receptors CCR1, CCR3, CCR4 and CCR5, belonging to seven transmembrane G-protein coupled receptor (GPCRs) family, it has the highest affinity to the CCR5. CCR5 is presented on the surface of T-cells, smooth muscle endothelial cells , epithelial cells, parenchymal cells and other cell types. After the binding of CCL5 to CCR5, phosphoinositide 3-kinase (PI3K) is phosphorylated and subsequently, the phosphorylated PI3K phosphorylates protein kinase B (PKB; also known as Akt) on the serine 473. Then, the Akt/PKB complex phosphorylates and inactivates a serine/threonine protein kinase GSK-3. After the CCL5/CCR5 binding, some other proteins are regulated as well. Bcl2 is more expressed and it induces apoptosis. Beta-catenin is phosphorylated and degraded. An important protein in the cell cycle, Cyclin D, is inhibited by inactivated GSK-3. CCL5 was first identified in  a search for genes expressed "late" (3–5 days) after T cell activation. It was subsequently determined to be a CC chemokine and expressed in more than 100 human diseases. RANTES expression is regulated in T lymphocytes by Kruppel like factor 13 (KLF13). The "CCL5" gene is activated after 3–5 days after activation of T-cell via TCR. This is different from the most of other chemokines which are released almost immediately after cell stimulation. Thus, CCL5 is involved in inflammation maintaining. It also induces expression of matrix metalloproteinases which are important for migration of cells into the site of inflammation . CCL5 may be also expressed by NK cells. SP1 transcription factor binds near to "CCL5" gene and mediates its constitutive mRNA transcription. The transcription factor is regulated by the JNK/MAPK pathway. Memory CD8+ T-cells are able to secrete CCL5 immediately after TCR stimulation, because they have a large number of preformed CCL5 mRNA in cytoplasm and its secretion is dependent only on translation. RANTES, along with the related chemokines MIP-1alpha and MIP-1beta, has been identified as a natural HIV-suppressive factor secreted by activated CD8+ T cells and other immune cells. The RANTES protein has been  engineered for "in vivo" production by Lactobacillus bacteria, and this solution is being developed into a possible HIV entry-inhibiting topical microbicide. Interactions. CCL5 has been shown to interact with CCR3, CCR5 and CCR1. CCL5 also activates the G-protein coupled receptor GPR75. CCL5 has two mechanisms of action according to its concentration. Clinical significance. CCL5 is involved in transplantations, anti-viral immunity, tumor development and numerous human diseases and disorders, for instance viral hepatitis or COVID-19. For instance, CCL5 level is higher during rejection of renal transplant. Importance of CCL5 is proved by various microbial strategies to avoid the  activity of chemokine. For instance, human cytomegalovirus (HCMV) express a viral chemokine receptor analogue US28, which sequesters CCL5. The chemokine is released by virus-specific activated CD8+ T-cells together with perforin and granzyme A. In cytotoxic T-cells (CTL) killing other cells via Fas/FasL interaction, CCL5 increases HIV-specific T-cell cytotoxicity. Moreover, it is considered that CCL5 in low concentration might inhibit HIV replication. It binds to CCR5 (as well as 2 other chemokines) on the surface of CD4+ T-cells. CCR5 is used by HIV as an entrance molecule to a cell. On the  contrary, CCL5 in high concentration might increase HIV replication. The chemokine is involved also in antiviral response against other viruses. For instance, it has been shown that CCL5 is highly expressed in mice infected by lymphocytic choriomeningitis virus. In CCL5 knock-out mice, virus-specific CD8+ T cells had reduced cytotoxic ability, reduced cytokines production and enhanced production of inhibitory molecules. It underscores the importance of CCL5 during chronic viral infection. Increased levels of CCL5 was discovered in lots of cancers. For instance in breast cancer, hepatocellular carcinoma, stomach cancer, prostate cancer and pancreatic cancer. CCL5 plays an important  role in various human disorders, such as atherosclerosis, COVID-19, SARS, atopic dermatitis, asthma, glomerulonephritis, alcohol liver disease, acute liver failure and viral hepatitis.