Chemokines and Chemokine Receptors: Positioning Cells for Host Defense and Immunity

Abstract

Chemokines are chemotactic cytokines that control the migratory patterns and positioning of all immune cells. Although chemokines were initially appreciated as important mediators of acute inflammation, we now know that this complex system of approximately 50 endogenous chemokine ligands and 20 G protein-coupled seven-transmembrane signaling receptors is also critical for the generation of primary and secondary adaptive cellular and humoral immune responses. Recent studies demonstrate important roles for the chemokine system in the priming of naive T cells, in cell fate decisions such as effector and memory cell differentiation, and in regulatory T cell function. In this review, we focus on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the organismic level in homeostasis, in acute inflammation, and during the generation and regulation of adoptive primary and secondary immune responses in the lymphoid system and peripheral nonlymphoid tissue.

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

“…1). We found that TILs generally expressed an activated chemokine receptor pattern 17 including high frequencies of CCR5 + , CXCR3 + and CXCR4 + (Fig. 1C).…”

“…While IL-8 may induce recruitment of T cells, T cells' extravasation and migration into peripheral tissues rely on selectin and integrin binding in concert with chemokine signaling to mediate rolling and firm adhesion to the endothelial wall. 17 , 36 Our xenograft model relies on stromal chemokines secreted by mouse endothelial cells and fibroblasts, and despite some sequence similarity and evolutionary conserved regions, there is a greater disparity, and these may not necessarily support T cell adhesion, extravasation and tumor infiltration. 37 In line with this, HEVs in human melanoma lesions have been shown to be major gateways for tumor infiltrating lymphocytes, 38 however lack of host immune cells in the NOG mouse model, and thus no orchestrating chemokines and cytokines, HEVs are most likely not produced in this model.…”

“…Among the common pro-inflammatory chemokine receptors are CCR5 and CXCR3, whereas site specific chemokine receptors such as CCR9 or CCR10 are upregulated on T cells primed in the mesenteric or skin draining LNs for subsequent homing to either gut or skin respectively. 16 , 17 …”

Lung Pericytes and Resident Fibroblasts

“…23 Expression profiling revealed that the chemotaxis pathway was more active in FoxD1 þ /Col1 À pericytes than in other lung fibroblasts, including higher levels of Ccl4 (macrophage inflammatory protein-1b), Cxcl2 (macrophage inflammatory protein-2), Ccl21 (secondary lymphoid-tissue chemokine), and Ccl5 (regulated on activation normal T cell expressed and secreted), which combined could attract neutrophils, monocytes, macrophages, dendritic cells, NK cells, and other classes of innate lymphocytes, and T cells (Figure 3). 10,63 The Col1 À pericyte subset also preferentially expressed a variety of immune sensing and response genes. Activation of the NLRP3 inflammasome to produce IL-1b is one of the strongest defenses against infections, but can also severely damage tissue and plays a highly pathogenic role in lung fibrosis.…”

Peripheral tolerance can be modified by altering KLF2-regulated Treg migration

“…In contrast to conventional T cells that recirculate between SLOs via blood and lymph, Tregs exhibit an expanded migratory pattern that includes tertiary tissues (14). A previous report demonstrated that KLF2 maintains naive T cells in a homeostatic migration pattern and, much like activated lymphocytes that quickly degrade this transcription factor, Klf2 excision causes quiescent T cells to vacate SLOs and enter peripheral tissues (15).…”