Lymphocyte responses to pathogens are triggered by engagement of antigen receptors with cognate pathogen-derived antigens presented by other cells. The initial priming encounter and the transmission of additional prerequisite costimulatory signals for lymphocyte activation occur in the specialized environment of lymphoid organs. Subsequently, the antigen-primed cells relocate to peripheral sites of infection and exert effector activities on renewed antigen challenge. To achieve this, the rare antigen-specific lymphocytes must travel between lymphoid and nonlymphoid organs via the blood and then exit the circulation to enter antigen-containing tissues. An essential step in this migration process is the adhesion of circulating lymphocytes to the endothelium of postcapillary venules, a complex, multistep cascade of events mediated by specialized adhesion receptors and chemoattractant pathways (Butcher 1991; von Andrian and Mackay 2000). In the first step, lymphocytes are captured ("tethering") and interact loosely with the endothelial cells ("rolling"). Tethering and rolling are mediated by members of the selectin family (L-, P-, and E-selectin) and their glycoprotein ligands (Ley and Kansas 2004); the two a4-integrins, a4p1 (VLA-4) and a4p7, can also mediate these initial adhesion steps in some cases (Alon et al. 1995; Berlin et al. 1995). Once T cells have begun to roll, they can undergo an "activation" step, which is usually (although not exclusively) mediated by chemokines, secreted polypeptides that are presented on the endothelial surface (Rot and von Andrian 2004). Chemokines bind to specific G protein-coupled receptors on rolling lymphocytes and trigger intracellular signals that lead to firm arrest ("sticking") of T cells on the endothelial surface. The sticking step is mediated by lymphocyte-expressed in-tegrins (e.g., LFA-1, a4p7, and a4p1), which undergo rapid, chemoattractant-induced conformational changes to assume an extended configuration. This transient structural shift greatly enhances the affinity of integrins for their endothelial ligands (e.g., ICAM-1, ICAM-2, VCAM-1, MAdCAM-1), most of which belong to the immunoglobulin superfamily (Carman and Springer 2003; von Andrian and Mackay 2000). Only when all steps are successfully taken can a T cell transmigrate ("diapedese") into a tissue.
Although the multistep adhesion paradigm applies to all leukocytes, the molecules involved in the different steps vary depending on the leukocyte population, tissue, and inflammatory context (Butcher and Picker 1996; Cys-ter 2003; Springer 1994; von Andrian and Mackay 2000). Recent advances in the field have unveiled several examples for this exquisite degree of specialization, in particular for T cell migration. At the same time, new observations highlight a previously unexpected degree of dynamic plasticity and malleabil ity in the trafficking behavior of effector/memory T cells. These findings open the possibility that the expression of tissue-specific traffic molecules on lymphocytes can be custom-modified, which might allow us to tailor cellular immune responses for therapeutic purposes.
In this review, we discuss the migratory pathways of naive as well as effector/memory T and B cells, including antibody-secreting cells (ASC, i.e., plasmablasts and plasma cells), with special emphasis on the mechanisms responsible for generating gut-tropic lymphocytes.
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