Expression of the chemokine receptor CCR2 on immature B cells negatively regulates their cytoskeletal rearrangement and migration

Abstract

In the bone marrow, B-cell development can be divided into different stages according to the rearrangement status of the immunoglobulin H (IgH) and IgL chain loci 1,2 and the expression of intracellular and surface-bound markers. The first cells expressing IgM at their surface during this developmental process are the immature B cells, 3 which leave the bone marrow and migrate to the spleen for their final maturation. 4,5 One of the most fundamental and important aspects of the immune system is its ability to recognize and respond to virtually any foreign antigen while maintaining strict unresponsiveness to self-antigens. For B cells, antigens encountered during the immature stage are likely to be self-antigens, and reactive clones are, therefore, subjected to negative selection through deletion, [6][7][8] receptor editing, 9,10 and anergy. 11 The selection process occurring within the immature B-cell compartments is also extended to the periphery, allowing deletion of virtually all B cells recognizing peripheral self-antigens outside of the bone marrow. 12 Immature B cells leave the bone marrow and migrate to the spleen where they can mature prior to antigen encounter. Like other naive lymphocytes, before their arrival in the spleen immature B cells might recirculate to nonsplenic secondary lymphoid organs, which are specialized tissues for collecting antigens, 13 or to sites of infection and inflammation. In these secondary lymphoid organs, where differentiation to mature cells does not occur, antigen encounter would lead to the death of the immature B cells and elimination of effective clones because of the negative selection process. Thus, it is imperative for B cells to home to the spleen and undergo a splenic maturation step before their release into the periphery.Homing of immature B cells to the spleen proceeds through the terminal branches of central arterioles to blood sinusoids of the marginal zone. 4,14 These immature B cells then penetrate the marginal zone sinus and reside in the outer zone of the periarteriolar lymphoid sheath (PALS), 15 where they become part of the B-cell-rich follicular areas. 15,16 At this site in the spleen, B cells are still immature and can be distinguished from their mature counterparts. 4,14,17 The transition from immature to mature B cell is characterized by a series of changes in surface marker expression and the activities of these B cells.Two populations of splenic B cells were recently identified as precursors of mature cells. Transitional B cells of type 1 (T1) are the recent immigrants from the bone marrow. Migrating T1 cells expressing B-cell receptors (BCRs) with high affinity to soluble self-antigens (Ags) in the blood are likely to die by negative selection by way of Ag-induced death. On entry to the spleen, T1 cells remain at the PALS, where additional bloodborne self-Ags trapped by the spleen may further drive negative selection. The remaining T1 cells develop into transitional B cells of type 2 (T2), which are found exclusively in the primary follicles of th...

Recruited inflammatory monocytes stimulate antiviral Th1 immunity in infected tissue

“…The chemokine receptor CCR2 is expressed on Ly6C hi monocytes and a subset of B cells, NK cells, NKT cells, pDC, and activated T cells (22)(23)(24)(25). However, following HSV-2 infection, the number of B cells, NKT cells, pDC, and activated T cells in the vaginal mucosa of CCR2 −/− mice were found to be comparable to that of WT mice (Fig.…”

CCL2 recruitment of IL‐6‐producing CD11b+ monocytes to the draining lymph nodes during the initiation of Th17‐dependent B cell‐mediated autoimmunity

“…CCR2 expression has been recently described on B cells and influences B cell functions [21,22]. To determine whether the altered autoantibody response in CCL2 -/-mice could be linked to CCR2 expression on B cells, we purified B cells from control mice and CCL2 -/-mice for studies of proliferation and production of antibodies.…”

Cytoskeletal Regulatory Gene Expression and Migratory Properties of B-cell Progenitors Are Affected by the ETV6–RUNX1 Rearrangement

“…These 2 axes are both involved in the modulation of CXCL12-mediated chemotaxis. Indeed, it has been reported that the expression of CCR2 negatively regulates the cytoskeletal rearrangement and migration of immature B cells and that the control of Bcell homing by CCR2 is mediated by its ligand, CCL2, which is secreted by B cells and downregulates the CXCL12 signaling cascade (40)(41). On the contrary, a synergistic effect of CXCR4 and the EGFR on promoting cancer metastasis has been reported (45).…”

“…These 2 receptors that negatively regulate the CXCL12 signaling cascade in BCP cells (39)(40)(41) are both upregulated in Ba/F3 cells after ETV6-RUNX1 induction [MFI increase average of CXCR7: 16%, range: 6%-27%, P < 0.05 ( Supplementary Fig. S2B); fold change of the Ccr2 gene: 12.55, P < 0.01 ( Supplementary Fig.…”