Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow

Abstract

Long-lived plasma cells in the bone marrow produce memory antibodies that provide immune protection persisting for decades after infection or vaccination but can also contribute to autoimmune and allergic diseases. However, the composition of the microenvironmental niches that are important for the generation and maintenance of these cells is only poorly understood. Here, we demonstrate that, within the bone marrow, plasma cells interact with the platelet precursors (megakaryocytes), which produce the prominent plasma cell survival factors APRIL (a proliferation-inducing ligand) and IL-6 (interleukin-6). Accordingly, reduced numbers of immature and mature plasma cells are found in the bone marrow of mice deficient for the thrombopoietin receptor ( IntroductionAntibody-secreting plasma cells are found in many tissues. However, the plasma cells that provide antigen-specific systemic antibodies for up to decades after immunization or infection predominantly reside in the bone marrow. [1][2][3] There are multiple lines of evidence that individual plasma cells can survive in humans and mice for many months at the least. [4][5][6][7] These long-lived plasma cells are important for maintaining protective antibody memory. However, autoantibody-secreting long-lived plasma cells are refractory to conventional immunosuppressive therapy and therefore represent a therapeutic challenge in autoimmune diseases. [8][9][10] Plasma cell survival is not cell-autonomous but depends on signals provided by their environment. The most potent plasma cell survival factors identified so far are a proliferation-inducing ligand (APRIL), interleukin-6 (IL-6), tumor necrosis factor-␣ (TNF-␣), stromal-derived factor-1␣, and signals transduced via CD44. [11][12][13][14] The bone marrow contains multiple microenvironmental niches that stimulate cellular proliferation, differentiation, and survival. [15][16][17][18][19][20] Each niche seems to support specifically one or a few particular hematopoietic stem or precursor cells. In this way, the sizes of these populations are limited by the number of available niches. 16,21 Similarly, competition for a limited number of survival niches may also control the turnover rate within the bone marrow plasma cell compartment. 12,[22][23][24] One or multiple niches may exist that have the capability to support the terminal differentiation and survival of bone marrow plasma cells. 25 As indicated by strong colocalization between a particular subtype of stromal-derived factor-1␣ ϩ reticular stromal cells and immunoglobulin G ϩ (IgG ϩ ) bone marrow plasma cells, the former seems to be an important element of plasma cell niches in that tissue. 26 However, in culture, bone marrow stromal cells support plasma cell survival only for a limited time, 13 suggesting that additional cell types contribute to the formation of plasma cell niches.In addition, it has been shown that macrophage-derived APRIL is required to support differentiation/survival of bone marrow plasma cells during early life, suggesting that factors ...

Immunological memories of the bone marrow

“…Stromal cells do not express BAFF or APRIL themselves, and it is obvious that those ligands of BCMA, the second essential survival signal for memory plasma cells, have to be provided by other cells, which we have termed “accessory” cells of the niche. Eosinophilic granulocytes,51 basophilic granulocytes,52 megakaryocytes,53 and monocytic cells54 have been described as accessory niche cells. Priorities and redundancies among these cell types have not finally been resolved 55, 56.…”

Quantification and three-dimensional microanatomical organization of the bone marrow

“…108 Plasma B cells are long-lived antibody-secreting cells that have been found in physical association to CAR cells, megakaryoctes, and eosinophils (eos). [109][110][111] (iv) Although a significant fraction (30%) of early lymphoid progenitors (Lin 2 IL7-ra 1 ) has been shown to lie proximal to mature, bone-lining osteoblasts, 48 the vast majority of phenotypically defined CLPs are in contact with IL-7-expressing CAR cells. 50 Quiescent CD4 1 memory T cells are found scattered throughout the BM in contact with perisinusoidal IL-7-secreting stromal cells.…”

Homing and Adhesion Patterns Determine the Cellular Composition of the Bone Marrow Plasma Cell Niche

“…If each cell type colocalized randomly with PCs, the colocalization frequencies per total surface area would be similar for each cell type. Normalized contacts were thus calculated as previously described (13). Briefly, the total cell surface area was calculated by multiplying the surface area of a single cell (calculated by using the diameter of each cell subset and assuming a circular shape) with the total cell number of the cell subset.…”

“…It remains unclear whether all VCAM-1-expressing cells participate in the BM niche or whether only those expressing CXCL12 do. MGKs were recently described as providing critical BMPC support based on a preferential colocalization with PC compared with granulocytes (13). Yet, only 30% (and as few as 10% in some mice) of BMPCs are close to MGKs, which produce only low levels of the PC survival factor a proliferationinducing ligand (APRIL) but are an abundant source of BM IL-6, which efficiently supports PC survival in vitro (3,16,17).…”

“…Several different BM cell types have recently been claimed as providing critical contributions to BMPC survival, including reticular stromal cells (7,8), osteoblasts (9), osteoclasts (10), Gr1 int CD11b + monocytes (11), eosinophils (12), megakaryocytes (MGKs) (13), and basophils (14). CXCL12-abundant reticular (CAR) cells, CXCL12 + reticular cells, and osteoblasts (15) were unambiguously demonstrated as key compartments of the BMPC niche when it was demonstrated that PCs lacking CXCR4 (the receptor for CXCL12) fail to home to the BM compartment (7).…”