Plasma cells provide humoral immunity. They have traditionally been viewed mainly as short-lived end-stage products of B-cell differentiation that deserve little interest. This view is changing, however, because we now know that plasma cells can survive for long periods in the appropriate survival niches and that they are an independent cellular component of immunological memory. Studies of the biology of plasma cells reveal a mechanism of intriguing simplicity and elegance that focuses memory provided by plasma cells on recently encountered pathogens while minimizing the 'fading' of memory for pathogens encountered in the distant past. This mechanism is based on competition for survival niches between newly generated plasmablasts and older plasma cells.

Maintenance of protective humoral immunity depends on the generation and survival of antibody-secreting cells. The bone marrow provides niches for long-term survival of plasma cells generated in the course of systemic immune responses in secondary lymphoid organs. Here, we have analyzed migratory human plasma blasts and plasma cells after secondary vaccination with tetanus toxin. On days 6 and 7 after immunization, CD19 ؉ / CD27 high /intracellular immunoglobulin G high (IgG high )/HLA-DR high /CD38 high /CD20 ؊ / CD95 ؉ tetanus toxin-specific antibodysecreting plasma blasts were released in large numbers from the secondary lymphoid organs into the blood. These cells show chemotactic responsiveness toward ligands for CXCR3 and CXCR4, probably guiding them to the bone marrow or inflamed tissue. At the same time, a population of CD19 ؉ /CD27 high /intracellular IgG high /HLA-DR low /CD38 ؉ /CD20 ؊ /CD95 ؉ cells appeared in the blood in large numbers. These cells, with the phenotype of long-lived plasma cells, secreted antibodies of unknown specificity, not tetanus toxoid. The appearance of these plasma cells in the blood indicates successful competition for survival niches in the bone marrow between newly generated plasma blasts and resident plasma cells as a fundamental mechanism for the establishment of humoral memory and its plasticity. IntroductionProtective humoral memory is conferred by stable titers of specific antibodies (Abs) and can last for years. 1 Although primary contact with an antigen (Ag) leads to the formation of Ab-secreting plasma blasts (PBs) with a lifespan of less than 1 week in extrafollicular foci and results in short Ab responses, 2 most Ab-secreting cells (ASCs) generated during secondary (memory) immune response leave the follicles of the secondary lymphoid tissues as PBs. Specific ASCs are later found in the bone marrow (BM), [3][4][5] mucosa-associated tissues, chronically inflamed tissues, 6 or, to a lesser extent, the red pulp of spleens, 7 with the phenotype of mature plasma cells (PCs) and a potential lifespan of more than 18 months. 3,8,9 Indeed, specific Ab titers, mostly of immunoglobulin G (IgG) and IgA subclasses, can be stable for years 10 and are produced mainly by resident PCs of the BM. 10,11 The survival of PCs within the bone marrow (BM) is not an intrinsic capability of these cells but, rather, is regulated by the local microenvironment, 7 which provides a limited number of survival niches for PCs. [12][13][14] Because Abs of the IgG subclass have only a half-life of 3 weeks, 12-14 the survival of PCs in the BM is prerequisite for the maintenance of Ab titers over long time periods (ie, protective immunity and memory). Release from secondary lymphoid organs, migration of PBs to the BM, and competition for the apparently limited number of survival niches with resident PCs generated earlier control the establishment and persistence of protective humoral memory.Chemokines and their receptors are crucial for the control of lymphocyte trafficking. In mouse, CX-chemokine-re...

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.