Recent results suggest that plasma cell longevity is not an intrinsic capacity, but depends on yet unknown factors produced in their environment. In this study, we show that the cytokines IL-5, IL-6, TNF-α, and stromal cell-derived factor-1α as well as signaling via CD44 support the survival of isolated bone marrow plasma cells. The cytokines IL-7 and stem cell factor, crucially important for early B cell development, do not mediate plasma cell survival, indicating that plasma cells and early B cells have different survival requirements. As shown in IL-6-deficient mice, IL-6 is required for a normal induction, but not for the maintenance of plasma cell responses in vivo, indicating that the effects of individual survival factors are redundant. Optimal survival of isolated plasma cells requires stimulation by a combination of factors acting synergistically. These results strongly support the concept that plasma cell survival depends on niches in which a combination of specific signals, including IL-5, IL-6, stromal cell-derived factor-1α, TNF-α, and ligands for CD44, provides an environment required to mediate plasma cell longevity.

Plasma blasts formed during memory immune responses emigrate from the spleen to migrate into the bone marrow and into chronically inflamed tissues where they differentiate into long-lived plasma cells. In this study, we analyze the chemokine responsiveness of plasma blasts formed after secondary immunization with OVA. Starting from day 4 and within ∼48 h, OVA-specific plasma blasts emigrate from spleen and appear in the bone marrow. Although these migratory cells have lost their responsiveness to many B cell attracting chemokines, e.g., CXC chemokine ligand (CXCL)13 (B lymphocyte chemoattractant), they migrate toward CXCL12 (stromal cell-derived factor 1α), and toward the inflammatory chemokines CXCL9 (monokine induced by IFN-γ), CXCL10 (IFN-γ-inducible protein 10), and CXCL11 (IFN-inducible T cell α chemoattractant). However, the responsiveness of plasma blasts to these chemokines is restricted to a few days after their emigration from the spleen, indicating a role for these molecules and their cognate receptors, i.e., CXCR3 and CXCR4, in the regulation of plasma blast migration into the bone marrow and/or inflamed tissues.

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IntroductionAntibodies secreted by terminal differentiated B cells are important in immune defense, 1 but also can contribute to the pathogenesis of autoimmune diseases. 2 On stimulation by antigen and CD40 signaling by T cells, naive B cells can form germinal centers yielding memory B cells expressing antibodies of higher affinities. 3 On a second contact with antigen, memory B cells can differentiate into proliferating antibody-secreting plasmablasts found in the extrafollicular areas of secondary lymphoid tissues. 4 These cells further differentiate into mature nondividing plasma cells either remaining within the tissues of their origin or accumulating in mucosa-associated tissues, bone marrow, and sites of inflammation. 5,6 Plasma-cell homing to different tissues is a crucial regulator of the strength and duration of humoral immune responses. Maintained antibody responses are associated with plasma-cell homing to the bone marrow. 7 Under pathologic conditions, longterm survival of plasma cells is also supported in chronically inflamed tissues. 8,9 The local production of antibodies by plasma cells resident at such sites is likely to be important in clearing pathogens. In individuals suffering from systemic inflammatory autoimmune diseases, disturbed plasma-cell localization is associated with the production of autoantibody titers refractory to conventional therapy. 10 During differentiation into plasma cells, B cells change their chemokine receptor expression profile. 5,6,11 Expression of C-C chemokine receptor type 9 (CCR9) and CCR10 allows homing of immunoglobulin A (IgA) plasma cells to mucosal tissues. 12,13 IgG ϩ plasma-cell precursors formed in a secondary immune response against systemic antigenic challenge migrate toward ligands for C-X-C motif chemokine receptor 3 (CXCR3) and CXCR4, likely allowing them to migrate to inflamed tissue and bone marrow, respectively. 14,15 Additionally, both chemokine receptors and their cognate ligands likely also play a role for the localization of activated B cells, plasmablasts, and plasma cells within secondary lymphoid tissues. Plasma cells surrounding the germinal centers are colocalized with CXCL12, the ligand for CXCR4. 16,17 In the draining lymph nodes, CXCL9 is produced by a subset of high endothelial venules (HEVs) surrounding the B-cell follicles. 18 Here, we show that in vivo, CXCR3 is expressed only on a fraction of human memory B cells, preferentially those expressing IgG1. Once induced, the expression of this chemokine receptor is maintained during plasma-cell differentiation. Thus, the information whether this chemokine receptor is used during an immune response seems to be part of the B-cell memory. On CXCR3 Ϫ B cells, interferon ␥ (IFN-␥), but not interleukin 4 (IL-4), IL-1␤, IL-6, IFN-␣, IFN-␤, or tumor necrosis factor ␣ (TNF-␣), induces the expression of this receptor. For that, IFN-␥ must be present before day 3 following activation of the B cells. In vivo, during this period, activated B cells are located within the follicular areas, colocalized ...