Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response

Abstract

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...

CMV‐specific central memory T cells reside in bone marrow

“…Interestingly, total numbers of T CM did not significantly differ between PB and BM, which suggests that recently activated T CM preferentially migrate or expand in BM. In this context a study is of interest showing that secondary vaccination resulted in the mobilization of resident nonvaccine-specific plasma cells indicating competition for BM niches [25]. It would be of interest to study whether similar phenomena could be observed for CMV-specific T cells.…”

Repression of IFN-γ Induction of Class II Transactivator: A Role for PRDM1/Blimp-1 in Regulation of Cytokine Signaling

“…In this case, PRDM1/Blimp-1 can mediate repression of CIITA at pIII to turn off the expression of MHC-II. However, a portion of plasma cells migrate to sites of inflammation (45)(46)(47). The expression of PRDM1/Blimp-1 in these plasma cells is likely to prevent the up-regulation of CIITA from pIV in environments of ongoing IFN-␥ production.…”

Immunological memories of the bone marrow

“…In humans (re)vaccinated against tetanus, a wave of newly generated plasmablasts is detectable between days 6 and 8 after vaccination in the blood. In transwell migration assays, these plasmablasts migrate toward CXCL12 gradients 46. Outside of this time window, only few plasmablasts and plasma cells are detectable in blood, and most if not all of them are obviously derived from mucosal immune responses 48.…”