Chapter 20 : Chemokines

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Early progress was made for those chemokines with unique selectivity for cells of the innate immune system, giving the impression that T and B cells are poor targets for chemokines. Of course, it is now thoroughly established that chemokine selectivity reaches well beyond monocytes and phagocytes, embracing all types of leukocytes, including T and B cells as well as hematopoietic progenitor cells. Recent exciting progress focuses on the recognition that certain G-protein-coupled receptors (GPCRs) also signal by G-protein-independent mechanisms. Recent reports demonstrated the involvement of chemokines in tumor metastasis, a finding that seems to be related to the chemokine-typical control of leukocyte traffic. In support, one group reported dimerization of chemokine receptors (such as CXCR4, CCR2, or CCR5) and suggested that higher-order structure formation is a prerequisite for chemokine receptor signaling. Although tissue cell recruitment and localization may be fundamental roles played by chemokines in tissue remodeling and secondary tumor formation, elucidation of leukocyte mobilization-unrelated functions is one of the major topics in current chemokine research. Importantly, changes in the diversity of local chemokines during ongoing inflammatory processes directly affect the composition of the inflammatory infiltrates and, as such, dictate disease evolution. Future challenges in chemokine research are related to tissue cell responses to chemokines and include the potential effect of chemokines on tissue cell growth and differentiation during organogenesis and tissue repair.

Citation: Moser B. 2004. Chemokines, p 397-416. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch20
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Remarkable diversity in chemokine function. Leukocyte chemotaxis is the prototype function of chemokines, which requires rapid and transient changes in cytoskeletal arrangements and adhesive interactions with extracellular matrices. Extravasation includes the transendothelial migration of bloodborne leukocytes, whereas chemotaxis is the directional movement of leukocytes along a chemoattractant gradient within the tissue. Chemokine-mediated cell migration as well as migration-unrelated functions may also affect hematopoiesis and aspects of exocytosis (and possibly other effector functions). Certain chemokines also function in tissue cells and may control, in part, secondary tumor formation, angiogenesis, and organogenesis. Finally, chemokines of viral or human origin play multiple roles in viral infections.

Citation: Moser B. 2004. Chemokines, p 397-416. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch20
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CCR5 and CXCR4 are the two major HIV-1 coreceptors.HIV-1 (as well as HIV-2 and SIV) requires CD4 and one of two chemokine receptors, termed HIV/SIV coreceptors, for entry into target cells, which include T cells and monocytes and macrophages (T/M). Coreceptor selectivity determines viral tropism; accordingly, CCR5 or CXCR4 usage defines R5 or X4 viruses. RANTES, MIP-1α, and MIP-1β with selectivity for CCR5, and SDF-1 with selectivity for CXCR4, inhibit target cell entry of R5 and X4 HIV/SIV, respectively, and are referred to as HIV/SIV suppressor factors. R5 HIV-1 particles predominate during viral transmission and the asymptomatic phase of the disease, whereas the appearance of X4 HIV-1 particles correlates with progression to AIDS.

Citation: Moser B. 2004. Chemokines, p 397-416. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch20
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Central role of T cells in the initiation of adaptive immune responses. The chemokines SLC and ELC direct the recruitment of CCR7-expressing peripheral blood T cells into secondary lymphoid tissues for colocalization in the T zone with CCR7 antigen-presenting cells. Antigen recognition and costimulation result in CD4 T-cell priming, characterized by expression of CXCR5 and certain costimulatory molecules, such as ICOS, and concomitant downmodulation of CCR7 and responsiveness to T-zone chemokines. CXCR5 characterizes T cells, which are nonpolarized T-helper cells with unique homing properties for B-cell follicles.Through contact with antigen-presenting B cells,T cells may develop into B helper T cells to support follicular B-cell activation and plasma cell or memory B-cell generation. Alternatively, contact with B cells induces differentiation of T cells into effector T-helper cells, such as cytokine-producing Th1 and Th2 cells, with newly acquired homing capability for inflammatory sites. Abbreviations:APC, antigen-presenting cell; BCR, B-cell antigen receptor; ICOS, inducible costimulatory molecule; ICOS-L, ICOS ligand; T, follicular B-helper T cell;T1,Th1 cell;T2,Th2 cell.

Citation: Moser B. 2004. Chemokines, p 397-416. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch20
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Generic image for table

The human chemokine system

Citation: Moser B. 2004. Chemokines, p 397-416. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch20
Generic image for table

Cellular distribution of human chemokine receptors

Citation: Moser B. 2004. Chemokines, p 397-416. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch20

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