CCL5

What is CCL5?

In the host immune system, chemokines are a group of signal proteins or small cytokines secreted by immunocytes, which are named for the ability to induce chemotaxis of nearby responsive cells. C-C motif ligand 5 (CCL5), also known as RANTES (regulated on activation, normal T cell expressed and secreted), is a chemotactic cytokine extensively released from T lymphocytes, natural killer cells, epithelial cells, platelets, as well as certain tumor cells.

Functionally, CCL5 is an inflammatory chemokine playing an active role in recruiting a variety of leukocytes into inflammatory sites. By reacting with chemokine receptors, such as CCR5, CCR3, and CCR1, CCL5 induces the activation and proliferation of partial natural killer cells collaborating with other cytokines produced by T cells. It has been indicated that CCL5 was an effective factor that suppressed the human immunodeficiency virus (HIV) entry into target cells. A great deal of studies has shown that increased expression of CCL5 was strongly associated with multiple human cancers, suggesting that CCL5/CCR5 might be a potential therapeutic target for cancer treatment.

Fig.1 Effects of the CCL5/CCR5 interactions in cancer. (Aldinucci, 2014)

CCL5 Secreted by γδ T Cell

In humans, a minor subset of T lymphocytes expressing a distinctive T-cell receptor (TCR) composed of a γ chain and δ chain are so-called γδ T cells, accounting <5% of the total T cells. Although the overall structures of the γδ T cells are similar to the common T cells (namely αβ T cells), the antigen recognition and functional mechanisms are subtly different. The secretion and chemotaxis of chemokines by αβ T cells have been extensively elaborated, whereas, little information is available on the chemokines secreted by γδ T cells.

Both in vivo and in vitro studies have revealed that γδ T cells produce a large array of cytokines and chemokines, exerting cytotoxic activity and effector functions. Several investigations indicated that γδ T cells express CCL5, which was an inflammatory chemokine involved in the anti-HIV infection. Activation Vγ9Vδ2 T cells with phosphoantigens induced the production of CCL5 and other β-chemokines, all of which are the natural ligands for the chemokine receptor CCR5. CCL5 produced by γδ T cells bound to CCR5, also known as HIV co-receptor, and blocked the HIV attachment and entry to the CCR5, thereby suppressed HIV replication. Moreover, the engagement of the natural killer receptor NKp30 resulted from the activation of Vδ1 T cells led to the increased production of CCL5, CCL3, and CCL4, which significantly inhibited HIV replication in vitro. Another research demonstrated that circulating memory γδ T cells, mostly Vγ2Vδ2 T cells, contained CCL5 mRNA in the cytoplasm in response to rapid chemokine responses to phosphoantigen stimulation.

Fig.2 Pleiotropic Recognition and Responses of γδ T cell. (Hayday, 2009)

References

1. Poccia, F., et al. Phosphoantigen-reactive Vgamma9Vdelta2 T lymphocytes suppress in vitro human immunodeficiency virus type 1 replication by cell-released antiviral factors including CC chemokines. The Journal of Infectious Diseases. 1990, 180(3): 858-861.
2. Hudspeth, K., et al. Engagement of NKp30 on Vδ1 T cells induces the production of CCL3, CCL4, and CCL5 and suppresses HIV-1 replication. Blood. 2012, 119(17): 4013-4016.
3. Hayday, A.C. γδ T Cells and the Lymphoid Stress-Surveillance Response. Immunity. 2009, 2(31): 184-196.
4. Tikhonov, I., et al. Human Vγ2Vδ2 T cells contain cytoplasmic RANTES. International Immunology. 2006, 18(8): 1243-1251.