Changing responsiveness to chemokines allows medullary plasmablasts to leave lymph nodes

Abstract

During T cell-dependent antibody responses lymph node B cells differentiate either to plasmablasts that grow in the medullary cords, or to blasts that proliferate in follicles forming germinal centers. Many plasmablasts differentiate to plasma cells locally, but some leave the medullary cords and migrate to downstream lymph nodes. To assess the basis for this migration, changes in the responsiveness of B cells to a range of chemokines have been studied as they differentiate. Naive B cells express high levels of CCR6, CCR7, CXCR4 and CXCR5. When activated B cells grow in follicles the expression of these chemokine receptors and the responsiveness to the respective chemokines is retained. During the extrafollicular response, plasmablast expression of CXCR5 and responsiveness to B-lymphocyte chemoattractant (CXCR5) as well as to secondary lymphoid tissue chemokine (CCR7) and stromal cell-derived factor (SDF)-1 (CXCR4) are lost while a weak response towards the CCR6 chemokine LARC is maintained. Despite losing responsiveness to SDF-1, extrafollicular plasmablasts still express high levels of CXCR4 on the cell surface. These results suggest that the combined loss of chemokine receptor expression and of chemokine responsiveness may be a necessary prerequisite for cells to migrate to the medullary cords and subsequently enter the efferent lymph.

Cutting Edge: Profile of Chemokine Receptor Expression on Human Plasma Cells Accounts for Their Efficient Recruitment to Target Tissues

“…Plasma cells from immunized mice demonstrated up-regulation of CXCR4 and down-regulation of CXCR5 and CCR7 (2,3). Furthermore, plasma cells in chimeric mice reconstituted with CXCR4-deficient fetal liver cells were mislocalized within the spleen, found in elevated numbers in the blood, and failed to accumulate in the bone marrow (2).…”

A Division-Linked Mechanism for the Rapid Generation of Ig-Secreting Cells from Human Memory B Cells

“…Thus, acquisition of CD38 expression may correlate with selection into a population of T cell stimulation-independent, rapidly proliferating plasma cell precursors, which contribute to an initial expansion of the selected population of ISCs (9,10,47,49,54). The rapidly dividing CD38 ϩ ISCs presumably then acquire altered homing characteristics, resulting in their migration to sites including bone marrow (55,56), where they undergo terminal differentiation to yield long-lived quiescent CD38 ϩ plasma cells (38,45,52,53,57,58). In this way, Ig produced by the selected ISCs will be sustained for long periods even after Ag clearance (2,14).…”

Dysregulation of chemokine receptor expression and function by B cells of patients with primary Sjögren's syndrome

“…In this context, it is well established that surface expression of chemokine receptors does not necessarily indicate their migratory functionality (32)(33)(34). Indeed, the responsiveness of chemokine receptors for their respective ligands is differentially regulated (e.g., by RGS proteins) during the orchestration of the migration of lymphoid subpopulations into anatomic compartments, their development, activation, and immune response (26,27,(31)(32)(33)(34)(35)(36).…”

“…Indeed, the responsiveness of chemokine receptors for their respective ligands is differentially regulated (e.g., by RGS proteins) during the orchestration of the migration of lymphoid subpopulations into anatomic compartments, their development, activation, and immune response (26,27,(31)(32)(33)(34)(35)(36). B cells from different developmental stages, e.g., developing bone marrow B cells (36), B cells leaving GC structures (33), and medullary plasmablasts leaving lymph nodes (34), have been found to express high levels of surface CXCR4 but were unresponsive to CXCL12.…”