CCL2

What is CCL2?

Chemokines or chemoattractant cytokines are a family of small functional proteins inducing cell activation, migration, chemotaxis, and signaling via binding to corresponding chemokine receptors. Since the first discovery in 1977, more than 50 chemokines and 20 chemokine receptors have been identified over decades. The known chemokines are grouped into four subfamilies: CXC, CC, C, and CX3C, according to the number and position of four conserved cysteine residues at the N-terminus. The chemokine (C-C motif) ligand 2 (CCL2), also named monocyte chemoattractant protein 1 (MCP1), is the first identified chemokine of the C-C chemokine family.

Human CCL2 is a 76 amino acid monomeric polypeptide that is primarily secreted by immunocytes, such as monocytes, macrophages, and other cell types related to immune responses. By binding to chemokine receptor CCR2, CCL2 induces a potent chemotactic activity and infiltration of a variety of immune cells, mainly monocytes, memory T lymphocytes, and natural killer cells. As one of the most extensively studied chemokines, CCL2 once has been recognized as a "tumor-derived chemotactic factor" that promoted tumor infiltration by monocyte and macrophage. And the CCL2/CCR2 signaling has been implicated in multiple pathogeneses associated with inflammatory responses and neoangiogenesis, such as multiple sclerosis, asthma, neuroinflammatory disorders, diabetes, even cancers, exhibiting significant clinical importance and promising as a target for the therapy development.

Fig.1 Graphical overview of the effects of CCL2 on myeloid cells apart from migration. (Gschwandtner, 2019)

CCL2: a Potent Chemoattractant for γδ T Cell

Gamma-delta T cells (γδ T cells) are a critical portion of "special" T lymphocytes characterized by the γδ T-cell receptor (TCR) on the surface, which are capable of recognizing and binding to a broad range of antigens or ligands without the presentation of major histocompatibility complex (MHC). Once activated by antigens, these γδ T cells induce multiple effector and cytotoxic activity by expressing a diversity of receptors and functional cytokines.

It has been indicated both in vivo and in vitro that γδ T cells exert a favorable cytotoxic effect on many different cancer types. The analysis of the migration of γδ T cells into tumors using the B16 melanoma model showed that the chemokine CCL2 and its corresponding receptor CCR2 were necessary for tumor lymphocyte infiltration both in vivo and in vitro. Compared with normal mice, CCL2 together with CCL12 were notably overexpressed and accumulated around the B16 tumor in γδ T cell-deficient mice. In vitro chemotaxis assay showed that human Vδ1 γδ T cells and murine γδ T cells up-expressed CCR2 constitutively, migrated toward CCL2-abundant B16 tumors based on the CCL2/CCR2 chemokine pathway. Moreover, γδ T cells play a critical role in Mesocestoides Corti infection and central nervous system immune responses through secreting chemokines (e.g., CCL2 and CCL3) which facilitate the migration of lymphocytes to the brain.

References

1. Gschwandtner, F., et al. More Than Just Attractive: How CCL2 Influences Myeloid Cell Behavior Beyond Chemotaxis. Frontiers in Immunology. 2019, 10: 2759.
2. Lança, T., et al. Protective Role of the Inflammatory CCR2/CCL2 Chemokine Pathway through Recruitment of Type 1 Cytotoxic γδ T Lymphocytes to Tumor Beds. The Journal of Immunology. 2013, 190(12): 6673-6680.
3. Cardona, A.E. et al. CC Chemokines Mediate Leukocyte Trafficking into the Central Nervous System during Murine Neurocysticercosis: Role of γδ T Cells in Amplification of the Host Immune Response. Infection and Immunity. 2003, 71(5): 2634-2642.