Elsevier

Seminars in Immunology

Volume 18, Issue 5, October 2006, Pages 297-304
Seminars in Immunology

Review
BLyS receptor signatures resolve homeostatically independent compartments among naïve and antigen-experienced B cells

https://doi.org/10.1016/j.smim.2006.07.001Get rights and content

Abstract

The BLyS family of receptors includes two cytokines, BLyS and APRIL; and three receptors, BR3, BCMA and TACI. Together, these regulate the size and composition of peripheral B cell pools. The multiplicity of ligand–receptor sets, in conjunction with differential receptor expression, alternative binding partners and disparate downstream signaling characteristics, affords the potential to establish independently regulated homeostatic niches among primary and antigen-experienced B cell subsets. Thus, BLyS signaling via BR3 is the dominant homeostatic regulator of primary B cell pools, whereas APRIL interactions with BCMA likely govern memory B cell populations. Short-lived antibody forming cell populations and their proliferating progenitors express a TACI-predominant signature. Further, within each niche, relative fitness to compete for available cytokine is determined by exogenous inputs via adaptive and innate receptor systems, affording intramural hierarchies that determine clonotype composition.

Introduction

Members of the tumor necrosis factor (TNF) superfamily play diverse roles in regulating the activities of both resting and activated lymphocytes [1]. This family includes two closely related cytokines, B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), both of which are now recognized as central players in B cell development and homeostasis. Through differential interactions with several receptors, these two ligands profoundly influence multiple aspects of B cell biology. Their activities include mediating the selection, differentiation and homeostasis of primary B cells; influencing the differentiation of activated B cells; and controlling the generation and longevity of memory B cells. These broad and largely B lineage-specific activities, coupled with clear relevance to both autoimmunity and neoplasia, have focused intense scrutiny on BLyS, APRIL and their corresponding receptors. This concerted activity has already yielded considerable insight into fundamental aspects of B cell biology and has revealed several promising therapeutic targets, prompting extensive review and commentary [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28].

Currently, the most extensively studied biological activities of BLyS family members are those associated with developing and primary B cells. This focus reflects the striking phenotypic impact that knockouts and transgenics for certain BLyS family members have on primary B cell pools, as well as the presumed relevance of these activities to tolerance and autoimmune disease. In contrast, the nature and mechanisms through which BLyS family members influence antigen-experienced B cell populations remain less extensively explored. Nonetheless, several mechanistic features drawn from studies to date are likely common to all of these interactions. Foremost, the notion of interclonal competition underpins our perception of how this family controls B cell survival and selection. This idea holds that pool sizes can be controlled by limiting the amount or availability of cytokine, such that when cytokine consumption equals availability, steady state pool size is achieved. Further, such competition implies that populations occupying independent homeostatic niches can coexist in the same physical space, so long as each population relies upon and competes for a different cytokine (e.g., APRIL versus BLyS). A second important feature of current understanding is that a B cell's ability to capture these signals is coupled to other cell-intrinsic signaling systems, including innate and adaptive immune receptors. Accordingly, signals via these exogenous sensing systems in aggregate determine a cell's relative fitness compared to others competing for occupation of the same niche. Finally, differential receptor binding activities, in combination with changing expression levels influenced by differentiation or cross-talk with other surface receptors, specifies the cytokine-delineated niche within which each B cell competes.

While these general features of BLyS family activities have been revealed through studies of newly formed and primary B cells, only now are analogous properties being defined within activated and antigen-experienced B cell populations. Herein, we first overview the BLyS family members and key aspects of their actions on primary B cell populations. This is followed by a discussion of how activation-driven shifts in BLyS receptor expression are signature events that establish separate, intramurally competing cohorts during the initiation, progress and resolution of immune responses.

Section snippets

BLyS family of receptors and cytokines

Because of simultaneous initial reports, BLyS is also known as BAFF, TALL-1, zTNF4 and THANK [29], [30], [31], [32]. Likewise, APRIL has several aliases: TRDL-1, TALL-2 and TNFSF13A [31], [33]. Similar to other TNF members, BLyS and APRIL are type II transmembrane proteins that are proteolytically cleaved to generate active soluble forms. In fact, APRIL appears to be available only in soluble form because cleavage occurs in the Golgi apparatus [34], although alternative splice forms with

BLyS receptor expression in naïve B cells and their progenitors

Current evidence suggests that BLyS family members play little role in early B lineage commitment and differentiation. Thus, B lineage subsets prior to the bone marrow immature stage (Hardy Fr E) show no BLyS binding activity [62], nor do they express detectable levels of any of the three receptors. In contrast, all B lineage subsets subsequent to successful light chain rearrangement and surface Ig expression can bind BLyS and express one or more of the BLyS family receptors.

Within the immature

BLyS–BR3 interactions govern TR success and primary B cell lifespan

Despite clear TACI expression among TR, FO and MZ B cells, these subsets all appear normal or increased in both TACI and APRIL deficient mice [64], [65], [66], indicating that APRIL–TACI interactions are not critical to the generation or maintenance of primary B cells. Nevertheless, more subtle developmental roles for this ligand–receptor pair, such as repertoire selection or differentiation rate, remain possible. In contrast, the BLyS–BR3 axis is vital to the development and homeostatic

BLyS receptor expression changes among antigen-experienced B cells

While the necessity for BLyS–BR3 signaling among naïve B cells is well-documented, the exact roles played by BLyS family members in activated cells continue to unfold. B lymphocytes express a variety of surface receptors that govern the likelihood of activation and induction of primary humoral responses. Ligation of the prototypical B cell surface protein, the B cell receptor (BCR), results in widely divergent outcomes based on the avidity and extent of BCR–ligand interaction per se, as well as

Distinct BLyS receptor signatures are displayed by GC and memory subsets generated during TD responses

TD immunization elicits both rapid plasma cell differentiation and antibody secretion, as well as the initiation of germinal centers within the splenic B cell follicles [85], [86], [87], [88], [89], [90]. During the GC reaction, these rapidly dividing B cells undergo somatic hypermutation, generating novel BCR specificities. Those B cells expressing BCRs with a high affinity for antigen relative to the other cells in that GC are selectively preserved, while cells with mutations that either

Short-lived AFCs and their immediate progenitors in both TD and TI responses display predominant TACI expression

In contrast to the kinetics of cells destined for memory compartments via GC mediated selection and differentiation, AFCs are formed early in TD responses and wane rapidly. Interestingly, these cells express a unique BLyS receptor signature that is opposite that seen in GC cells: TACI is markedly up-regulated whereas BR3 is down-regulated (Fig. 1). Interestingly, rapid expansion and differentiation into AFCs are hallmarks of TI responses, and a similar BLyS receptor signature is observed among

Summary and perspective

Further analyses of the BLyS family should yield an understanding of the molecular mechanisms that afford independent homeostatic control of B naïve and antigen-experienced pools. These insights should in turn yield the ability to precisely manipulate or intervene in these homeostatic processes, suggesting novel diagnostic, prognostic and therapeutic opportunities in immune deficiency, autoimmunity, neoplasia and vaccine development.

Acknowledgements

The authors gratefully acknowledge Drs. Jean L. Scholz, Avinash Bhandoola and David Allman for critical comments and insightful discussions. This work was supported in part by USPHS research grant AI054488 to MPC, a Goldie Simon Preceptorship from the Lupus Foundation of America (SE PA chapter) to JEC and USPHS training grants T32-AI-055428 and T32-RR-07063 to JEC and LST, respectively.

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