ReviewChemokines in tissue-specific and microenvironment-specific lymphocyte homing
Introduction
Chemokines were first recognized as a family of small protein molecules, induced by inflammation and capable of attracting inflammatory leukocytes (such as monocytes, activated T cells and neutrophils) [1]. More recent evidence, however, implicates them as key players coordinating lymphocyte traffic throughout the body during routine immunosurveillance and orchestrating movements through complex microenvironments during lymphocyte development and differentiation. The end result of these intricate homing processes is to promote proper cell positioning and cell–cell interactions, helping towards a regulated immune response. Here we focus on recent studies that illustrate the participation of chemokines in tissue-selective lymphocyte homing, a process central to regional immune responses; we also briefly discuss some emerging insights concerning chemokine receptor expression in the thymus.
Section snippets
Chemokines in lymphocyte/endothelial-cell recognition
Chemokines and other ligands of Gαi-coupled receptors have been long known for their ability to mediate leukocyte chemotaxis and diapedesis. However, chemokines have a separate but equally important role in the complex process by which cells traveling at high speed under the shear forces of the circulation ultimately enter a tissue. When blood lymphocytes initiate the homing process by tethering and rolling on endothelium of high endothelial venules (HEVs) [2], they do not come to a stop unless
CCR7 as a homing receptor for secondary lymphoid organs
CCR7 (EBI-1/BLR-2) was first implicated as a potential mediator of adhesion triggering for cells homing through HEVs when it was discovered to be the receptor for SLC 10••, 11, a chemokine expressed at the mRNA level within HEVs of lymph nodes and Peyer’s patches [12••]. SLC triggers integrin-dependent adhesion of most peripheral blood lymphocytes under shear in vitro 6••, 7 and is displayed to passing lymphocytes at the endothelial surface 13••, 14••.
Homing of memory lymphocytes to nonlymphoid tissues
Although trafficking of naive T lymphocytes is largely restricted to secondary lymphoid organs, memory T cells are found at low levels in every tissue of the body and are preferentially recruited to extralymphoid (‘tertiary’ lymphoid) sites of inflammation. Moreover, memory cells display striking tissue selectivity of homing (reviewed in 23•, 24). The best-studied lymphocyte populations targeted to specific nonlymphoid tissues are the cutaneous or skin-homing population — defined by its
Chemokines and the homing of Th1/Th2 cells
An effort has been made over the past few years to associate expression of particular chemokine receptors with the cytokine secretion phenotype of particular T cell subsets (reviewed in [38•]) and such associations are apparent between cultured Th1 and Th2 cell lines generated under prescribed conditions in vitro. However it now appears that Th1- and Th2-associated chemokine receptor expression patterns from cultured/polarized cells are not necessarily maintained under physiological conditions
Chemokines and the organization of lymph nodes
The observation of disorganized lymphoid organs in CXCR5- or CCR7-deficient animals 20•, 40 strongly supports the notion that chemokines are instrumental in development and maintenance of the strictly segregated microenvironments characteristic of secondary lymphoid organs and in the movement of lymphocytes in and out of these areas. One example, a type of in-vitro-polarized T cell that normally homes to the outer PALS (periarteriolar lymphoid sheath) near the B cells zones of spleen, clusters
Conclusions
Since 1998, there have been three major conceptual advances in our view of chemokines and the immune system: firstly, the first direct experimental evidence demonstrating a role for chemokines in vascular recognition at the level of integrin-dependent adhesion triggering and arrest; secondly, the first examples of a role for chemokines in specialized tissue-specific lymphocyte homing and thus in defining and segregation of regional immune responses; and, thirdly, implication of chemokines in
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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