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Review
. 2015 Dec;1362(1):176-87.
doi: 10.1111/nyas.12825. Epub 2015 Jul 20.

B cells in the aging immune system: time to consider B-1 cells

Affiliations
Review

B cells in the aging immune system: time to consider B-1 cells

Nichol E Holodick et al. Ann N Y Acad Sci. 2015 Dec.

Abstract

The investigation of immune senescence has uncovered many changes in B cell development, maintenance, and function with increasing age. However, most of these studies have focused on conventional B cell subsets in the spleen. The B-1 cell subset is an essential arm of the innate immune system, which in general has been understudied in terms of immune senescence. Here, we review what is currently known about B cells during aging and go on to describe why B-1 cell biology is an important component of the aging immune system in the context of diseases that most affect the aged population.

Keywords: B cells; B-1 cells; aging; senescence.

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Figures

Figure 1
Figure 1
B cell development. B cell development begins with hematopoietic stem cells (HSCs) and continues through a series of differentiation steps dictated by expression of transcription factors, cytokines, and cell surface receptors. Long-term repopulating HSCs (LT-HSCs) and short-term HSCs (ST-HSCs) are named for their capacity to self-renew. The HSCs first differentiate into multipotential progenitors (MPP). Upon signaling through Flt-3, the MPPs differentiate into lymphoid-primed multipotential progenitors (LMPP), which differentiate into common lymphoid progenitors (CLP) upon Flt-3 and IL-7 signaling. Induction of the transcription factors E2A and EBF mark the differentiation of the CLP into a pre-pro B cell, commonly referred to as fraction A. E2A and EBF allow immunoglobulin rearrangement to begin, which is necessary for the development of B cells. Proper immunoglobulin rearrangement allows for the B cell to progress though each stage of differentiation, ending in a naive B cell, which can migrate into the periphery. Each stage of B cell development is marked by specific gene expression and surface marker expression as shown.
Figure 2
Figure 2
The aged developing and mature B cell pools. Both cell-intrinsic and cell-extrinsic changes occur throughout the stages of B cell development ranging from pre-lymphoid commitment (HSCs) to immature B cells. The mature B-2 cell pool in aged mice consists of follicular (FO) B cells, marginal zone (MZ) B cells, and age-associated B cells (ABC). Black arrows depict the relative increase or decrease in the differentiation subsets leading to mature B cell development. The asterisk (*) above fraction B/C denotes additional changes in the cells in the aged, which include decreased RAG and E2A expression.
Figure 3
Figure 3
B-1 cell development and maintenance with age. Building upon the model proposed by Motecino-Rodriguez and Dorshkind, we add what is currently known about the distinct waves of B-1 cell development leading to an adult pool of B-1a cells and propose extending the model to encompass changes with increasing age. (1) During the first wave of development, B-1 cell progenitors (AA4.1+LinCD45Rlow/−CD19+) are derived from yolk sac (YS) and para-aortic splanchnopleura (PSp) endothelium, before the emergence of HSCs. Whether this first wave of B-1 cells contributes to the adult pool of B-1 cells is still being examined. (2) The fetal liver and bone marrow is the site of the second wave of development. Current data has shown that HSCs are capable of giving rise to B-1 cells during fetal life, whereas HSCs present in the adult bone marrow are significantly less efficient at producing B-1 cells. It is not yet known whether HSCs have specified differentiation potential or if they lose their potential to produce B-1 cells in the adult. To indicate these possibilities, we have chosen a different color for HSCs producing B-1 cells during fetal life (green) versus those giving rise to B-2 cells (gray), which have limited development during fetal life. It has been shown that there is commitment to either B-1 or B-2 lineage at the CLP stage. Our recent results demonstrate that AA4.1LinCD45RCD19 fetal liver cells (NEG, light green circles) give rise to B-1 cells with increased diversity (abundant N-additions) upon transfer into adult SCID mice, whereas transfer of the fetal liver–derived B-1 cell progenitors (AA4.1+LinCD45Rlow/−CD19+) into adult SCID mice yields B-1 cells with limited N-region additions. These results suggest that an earlier population may differentiate into B-1 cell progenitors giving rise to more than one type of B-1 cell progenitor (red circle versus light blue circles), although whether this happens physiologically is not known. Either way, B-1 cells that develop during fetal and neonatal life have limited N-additions. (3) The third wave of development occurs in the adult bone marrow and mainly yields B-2 cells. We hypothesize that a possible mechanism of non-HSC–dependent B-1 cell development during adult life might occur via the NEG population of fetal liver cells that have migrated to the adult bone marrow. Furthermore, this adult development of B-1 cells would produce B-1 cells with increased N-additions, contributing to the change in B-1 cell –derived natural IgM with age.

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