Chemokine control of lymphocyte trafficking: a general overview

Abstract

Chemokines are a large family of small, generally secreted polypeptides which guide lymphocyte movement throughout the body by controlling integrin avidity and inducing migration. Here, we look at recent, exciting findings on chemokine function throughout lymphocyte development and co-ordinated T and B cell migration during immune responses. Finally, we will review data on the regional control of immunity by tissue-specific chemokine receptors on effector/memory lymphocytes.

Figure 1

CKR expression during postnatal thymocyte maturation. Blood-borne immature thymocyte precursors enter thymus by poorly defined adhesion pathways in blood vessels at the corticomedullar junction (CMJ). At least three CKR (CCR7, CXCR4, CCR9) were described independently to mediate migration and/or retention in the subcortical zone (SCZ), where massive proliferation takes place. Positively selected DP cells increase CCR7 expression, which allows translocation to the cortex. SP thymocytes exit thymus via CCR7- or S1P₁-dependent pathways to join the peripheral T cell pool. Despite multiple chemokine–CKR interactions during thymocyte development, no single CKR has been found thus far to be indispensable for T cell generation. Thymocytes and mature T cells are labelled green in this and subsequent figures. Please refer to text for more details. Adapted from Witt and Robey. DN: double negative cells; DP: double positive cells; SP: single positive cells.

Figure 2

Chemokines during physiological lymphocyte homing to secondary lymphoid organ. (a) Multistep adhesion pathways of T and B cells in the microcirculation of peripheral lymph nodes and Peyer's patches microcirculation. After l-selectin-mediated tethering and rolling of blood-borne T cells along peripheral node addressin (PNAd), endothelium-presented CCL21 and CCL19 bind CCR7 on rolling cells and rapidly trigger signals that are transmitted to integrins such as LFA-1. CKR-mediated signals induce conformational changes on integrins, resulting in affinity up-regulation and firm adhesion to ICAM-1 and-2. Adherent T cells transmigrate into the surrounding lymphoid tissue and accumulate in the T cell area, attracted by CCR7 ligands expressed in this microenvironment. B cell (labelled yellow in this and subsequent figures) adhesion in PLN venules additionally relies on CXCR4- and potentially CXCR5-dependent signals. Firm lymphocyte arrest in PP venules involves α4β7 integrin–MAdCAM−1 interactions during rolling and firm arrest, and in the case of B cells, CXCR5. After transmigration, B cells accumulate in CXCL13-expressing B cell follicles. (b) Lymphocyte homing to spleen white pulp. T and B cells are released in sinuses located in the marginal zone and red pulp, from where they are attracted via G-protein-dependent signals towards the T cell area. In the case of T cells, this signal probably derives from CCR7 ligands, whereas in the case of B cells, both CCR7 and CXCR5 ligands might contribute to this migration. After a short delay, B cells continue their migration into CXCL13-expressing B cell follicles, whereas T cells are held back in the T cell area. Please refer to text for more details. EC: endothelial cells; LFA-1: lymphocyte function-associated molecule-1, α_Lβ₂; PNAd: peripheral node addressin; ICAM-1: intracellular adhesion molecule-1; MAdCAM-1: mucosal adhesion cellular adhesion molecule-1; MZM: marginal zone macrophages; MZB: marginal zone B cells.

Figure 3

Chemokines during immune responses. (a) Upon Ag encounter, T cells transiently increase CXCR5 expression while B cells increase CCR7 expression. Balanced responsiveness to CXCR5/CCR7 ligands results in Ag-specific T-B cell encounters at the T–B cell area border. In the spleen, inflammatory stimuli decrease S1P signalling in MZ B cells, allowing accumulation of MZ B cells in CXCL13-expressing B cell follicles. (b) Regional control of chemokine and adhesion receptor expression on effector T cells. Peyer's patches (PP) DC produce retinoic acid, which is required for imprinting of gut tropism via CCR9 and α4β7 up-regulation while suppressing skin-homing receptors. In contrast, peripheral lymph nodes (PLN) DC direct skin tropism on activated T cells by increasing CCR4/10 and selectin ligand expression in what appears to be at least in part a default mechanism. (c) Chemokine control of germinal centre (GC) anatomy. CXCR4 mediates centroblast accumulation in GC dark zones while CXCR5 is required for proper orientation of light–dark zones towards T cell areas. It is probable that CXCR5 is also dependent for centrocyte migration towards light zones, where follicular T helper cells participate in providing centrocyte help. Please refer to text for more details. DC: dendritic cell; FDC: follicular dendritic cell; CC: centrocyte; CB: centroblast; T_FH: follicular helper CD4 T cell.