ReviewPhenotypic and functional heterogeneity of human memory B cells
Introduction
Immunological memory represents a highly effective mechanism to ensure quick protection against prevalent infections. B cell memory is generally viewed as supported by two cellular compartments: plasma cells, responsible for the production of antibodies (effector memory) and memory B cells which would represent precursors (central memory) capable of generating and replenishing the plasma cell compartment through a combination still incompletely understood of antigen-dependent and -independent mechanisms [1], [2], [3], [4]. This view is certainly valid when B cell effector functions are limited to the production of antibody. Yet, it is also incomplete as it fails to incorporate important effector and regulatory functions that may be played by “central” memory B cells (antigen-presentation, T cell and dendritic cell regulation and cytokine and chemokine production) [5], [6], [7]. When these critical B cell functions are considered, it can be postulated that effector memory is mediated by both plasma cells (through the production of antibodies) and by memory B cells (mostly through the production of cytokines). In turn, central memory B cells would be responsible not only for the generation and replenishment of plasma cells but also for the generation of distinct subsets of effector B cells. It is also possible that central memory B cells could play distinct regulatory roles.
Of note, the same properties of memory cells that are desirable for protective immune responses (long lifespan, prompt and enhanced responses to activation and ability to stimulate T cells) may be deleterious when it comes to avoiding chronic autoimmunity. Thus, once tolerance is broken in the B cell compartment, autoimmune memory would tend to persist (facilitated by availability of self antigens), could be easily reactivated and could break tolerance in the T cell compartment thereby providing a mechanism for further diversification and amplification [8], [9]. Given that substantial autoreactivity can be detected even in the IgG memory compartment of healthy subjects [10], it seems obvious that protective (anti-microbial) and potentially pathogenic (autoreactive) memory B cells must have different properties and be controlled by distinct regulatory mechanisms.
With regard to surface phenotype, substantial heterogeneity amongst human memory B cells has been documented by many studies including our own. Indeed, despite initial descriptions of CD27 as a universal marker of human memory cells, we and others have described memory populations that lack expression of CD27 and may be substantial in SLE and in some infections such as RSV [11], [12], [13], [14]. As discussed in this review, additional heterogeneity of memory B cells can also be demonstrated on the basis of the expression of CD38, CD21, CD24, CD19, B220, FcRH4 and CD25 [12], [15], [16], [17].
In addition to surface phenotype, the heterogeneity of human memory B cells can also be documented by: (1) differential regulation in autoimmune diseases and infections; (2) different repopulation kinetics after B cell depletion therapy (BCDT); (3) differential impact of other biological therapies; (4) different in vivo doubling times and half-life as documented by heavy water labeling (our own preliminary data indicating that CD27− memory cells have a much longer doubling time than CD27+ memory cells).
Importantly however, the actual functions of memory B cell subsets remains to be understood in terms of their relative participation in protective and autoimmune responses and in terms of their specific effectors and regulatory functions including cytokine production, antigen presentation and ability to differentiate into plasma cells. Also currently unknown is whether specific memory B cell subsets have different participation in central memory (understood as precursors of effector B cells and plasma cells) versus effector memory (defined as cytokine production). It is worth noting however that there is significant literature to support the ability of memory cells to produce abundant cytokines (TNF and lymphotoxin) with patterns different from naïve B cells (IL-10). Different studies also indicate that cytokine production by B cells may be relevant to human autoimmune diseases including SLE and MS. Finally, preliminary evidence indicates that excess production of pro-inflammatory cytokines by B cells may be reversed by BCDT in patients with MS [18].
Section snippets
Memory B cell heterogeneity
As recently discussed by others [19], our understanding of the diversity of memory B cell populations is hampered by pre-conceived notions of their surface phenotype, function and cellular and anatomical origin. Thus, the strict definition of a memory cell as one expressing isotype-switched, somatically mutated antibodies and generated through a T cell-dependent germinal center reaction would exclude important memory responses mediated by unswitched and/or unmutated B cells that at least in
Current schemes of classification of human memory B cell populations
By and large, the analysis of human B cell populations by flow cytometry has thus far relied on the expression of four major surface markers: CD19, IgD, CD38 and D27. With this four-color approach, two major classification schemes can be produced depending on the relative expression of either IgD and CD38 or IgD and CD27 (Fig. 1). Thus IgD/CD38 staining provides the so-called Bm1–Bm5 classification and can be used to identify multiple subsets in the human tonsil including: virgin naïve cells
Substantial additional complexity of human memory cells as revealed by multi-chromatic flow cytometry
In addition to the aforementioned classification schemes, human B cell subsets can also be defined by the surface expression levels of CD24 and CD38 (naïve, memory, GC, transitional B cells and plasmablasts). However, how the subsets defined by one classification scheme relate to those subsets defined by other schemes is not often clear. Hence, we have developed six different 10-color flow cytometry panels which provide a comprehensive phenotypic analysis of human B cell subsets and reveal
Anatomical distribution of human memory B cell subsets: The conundrum of the human spleen marginal zone and its equivalents
One of the main challenges in the study of human memory B cells is to understand their localization, phenotype and function of different subsets in the locales where they are generated in the course of orchestrated immune responses, where they reside as selected resting memory cells (in both cases presumably in the secondary lymphoid tissues although the contribution of the bone marrow needs to be more thoroughly assessed), and where they are recruited or generated as activated effector cells
Kinetics and homeostasis of memory B cell subsets: lessons from clinical situations and BCDT
The importance of elucidating human memory B cell heterogeneity is highlighted by our findings and those of others that certain memory subsets are preferentially expanded in particular clinical situations. Moreover, such studies have provided insight into the potential origin of diverse subsets and their dynamic generation in peripheral lymphoid tissue.
As shown by different groups, SLE patients display an expansion of switched memory in the peripheral blood which as previously discussed, is
Immuno-modulatory and effector functions of human memory B cells
While usually overshadowed by the production of antibodies, the ability of B cells to play important antibody-independent functions is well documented [5], [6], [7], [115]. These antibody-independent functions prominently include cytokine and chemokine production and antigen presentation. Through these functions B cells can profoundly influence the formation and organization of secondary lymphoid tissues and T cell development, activation and function [116], [117], [118], [119], [120], [121].
Summary
Experimental evidence continues to accumulate indicating that B cell memory is rather complex and includes T-cell dependent and independent memory, isotyope-switched and unswitched, mutated and unmutated memory B cells. It may also include a “natural” memory at least in part provided by conventional MZ B cells, several adaptive memory populations and possibly adaptive memory B cells that acquire marginal zone-like properties. Functionally, effective and appropriate (i.e., protective and
Acknowledgements
The work in this paper is supported in part by grants: R01 AI049660-01A1, U19 Autoimmunity Center of Excellence AI56390, and Center for Biodefense of Immuno-compromised Populations N01-AI50029 (IS); NIH-NIAMS K08AR048303, the Lupus Foundation of America, and the Alliance for Lupus Research (JA); NIH-NIAID K23A167501-01A1 (FEL).
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