Chemokines are classified into four families on the basis of structural differences: CXCL, CCL, XCL, and CXC3CL. Chemokines can also be classified as pro-inflammatory (red), homeostatic (green), and mixed function (yellow). Chemokines bind to a subfamily of seven-transmembrane G-protein-coupled receptors, which are classified as CXCR, CCR, XCR, and CX3CR on the basis of the class of chemokines they bind. Many, but not all, of the chemokine-chemokine receptor networks that coordinate immune modules are represented here. The connection between receptors and cell types on which they are expressed is indicated by the ‘circuit’ representation of lines and connecting nodes. To connect chemokines and their receptors to target cells, follow a horizontal line and turn on a vertical one at each node; the rhomboids (diamond shapes) link vertical lines to the cell type. Note that most chemokine receptors can bind multiple chemokines. Modified from Mantovani et al., Nat. Rev. Immunol. 2006, 6:907-918.
Fig. 11.8 Chemokine networks coordinate the interactions of innate and adaptive immune-cell populations.
In addition to the general and tissue-specific changes in trafficking molecules induced during effector T-cell differentiation, there is subset-specific expression of chemokine receptors that accompanies the loss of CCR7 expression. This results in distinct patterns of chemokine receptor expression by TH1, TH2, and TH17 cells that guide their differential recruitment to sites of inflammation contingent on the local patterns of inflammatory chemokines induced by the innate immune response to different types of pathogens (Fig. 11.9). For example, TH1 cells express CCR5, which is also expressed on monocytes that mature into macrophages as they enter the inflammatory site. Thus, both TH1 cells and the innate effector cells whose effector functions they enhance are recruited to the same tissue site by the same chemokines (see Fig. 11.8). As is the case for many other chemokine receptors, CCR5 has multiple ligands (CCL3, CCL4, CCL5, and CCL8), which may be induced by different cellular sources and by different pathogens targeted by type 1 immunity. Some of these are produced by activated macrophages themselves following their recruitment to the inflammatory site. This provides a feed-forward mechanism by which the emerging innate response is amplified and then contributes to the recruitment of TH1 cells, which then provide antigen-dependent ‘help’ to further activate the macrophages, as we discuss in the next section. TH1 cells also express CXCR3, which is shared by NK cells and cytotoxic CD8 T cells. In response to CXCR3 ligands— CXCL9 and CXCL10—these cells are recruited to the same inflammatory site to coordinate the cell-mediated killing of targets infected by intracellular patho gens, such as Listeria monocytogenes, or certain viruses.