A T cell (blue), a type of lymphocyte, in contact with
the dendritic cell beneath it. Credit: Lawrence Berkeley
What do monocytes, lymphocytes, and neutrophils all have in common? Well, yes, they are all leucocytes and part of our immune system, but what else? They all can be prompted to migrate to the site of infection by a specific class of cytokines known as chemotactic cytokines, or chemokines for short. These chemokines are made by a wide variety of cell types, including macrophages, various blood cells, epithelial cells, endothelial cells, and, of particular interest here, by numerous human tumor cell lines, melanoma cells, and liver cells infected by hepatitis C virus. Some chemokines function to direct cell migration during normal processes, such as embryogenesis, lymphoid organ development, and haematopoiesis. The chemotactic responses they incite can be quite specific, with different cell populations responding to different chemokines, of which there are more than 40, classified into four families. They’re all small proteins (~8–10 kDa), all have the same characteristic structure, and all are homologous, with 20–50% amino acid identity. That much divergence in sequence provides plenty of opportunity for specificity of action.
Diagram showing a chemokine with its typical,
conserved fold within the lumen of a blood
vessel. The chemokine is interacting with a
glycosaminoglycan (GAGs present on the sur-
face of an endothelial cell lining the vessel.
From there, the chemokine is presented to the
seven-transmembrane domain signalling recep-
tor in the membrane of a passing leucocyte.
Receptor binding involves multiple regions of
both the chemokine and the receptor. The key
motifs involved are labeled here. Source.
The receptors for these intercellular communication molecules lie on the surface of the leucocytes, and they, too, are a diverse lot—at least 19 different ones are known. They also have their own commonality: a structure with seven-transmembrane domains to securely anchor them in the cell membrane and a coupled G protein. Along comes their cognate chemokine secreted by some cell at the site of infection. The chemokine binds to the receptor, and the coupled G protein initiates an intracellular signaling cascade that can affect multiple pathways. Actually, it’s a little more complicated. Chemokines bind first to the surface of the endothelial cells lining the blood vessel via GlycosAminoGlycans (GAGs). This keeps them from being washed away by the bloodstream and positions them for binding to receptors on passing leucocytes. (See the figure to the left.) For an effective inflammatory response, the leucocytes also need to be shown which way to go. The GAGs are essential here, too. The chemokines bound to the GAGs along the blood vessel establish a stationary chemokine concentration gradient around the site of infection. When a leucocyte binds a chemokine, it ‘crawls’ along the chemotactic gradient and then undergoes diapedesis to migrate into the tissue space.