The role of APRIL and BAFF in lymphocyte activation

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The TNF family ligands BAFF (also called BLyS) and APRIL regulate lymphocyte survival and activation. BAFF binds to three receptors, BAFF-R, TACI and BCMA, whereas APRIL interacts with TACI, BCMA and proteoglycans. The contribution of BAFF and APRIL to B-cell and plasma-cell survival, CD154 (CD40L)-independent antibody isotype switching, germinal center maintenance, T-dependent and T-independent antibody responses, and T cell co-stimulation are relatively well understood. Constitutive BAFF produced by stromal cells determines the size of the peripheral B cell pool, whereas inducible BAFF produced by myeloid and other cells supports local survival of B lymphocytes and can be associated with development of autoimmunity when deregulated.

Introduction

TNF family members are type II transmembrane proteins that spontaneously form homotrimers and are membrane-bound or solubilized ligands for a cognate family of receptors. APRIL (a proliferation-inducing ligand) and BAFF (B-cell activation factor of the TNF family; also called BLyS or TALL-1) were initially identified on the basis of their homology to TNF, although there were few clues as to their physiological functions. These ligands, however, were rapidly implicated in several immunological phenomena that previously lacked a satisfactory molecular explanation, such as peripheral B-cell survival, CD154 (CD40L)-independent antibody isotype switching and the induction of self-reactive B cells. Merging these different fields has proven rather successful and has provided an increasingly coherent overview of the action of BAFF and APRIL in the immune system. This knowledge will certainly translate into therapeutic applications in the near future.

This review focuses on structural and functional aspects of the BAFF–APRIL subfamily, and attempts to describe the roles played by the many receptors of this subfamily in the immune function of healthy individuals.

Section snippets

The interactions of BAFF and APRIL with their receptors and binding partners

Ligand–receptor interactions within the BAFF–APRIL subfamily of TNF ligands are both redundant and specific; for example, BAFF binds to BAFF-R, TACI (transmembrane activator and CAML interactor) and, with lower affinity, to BCMA (B-cell maturation antigen), whereas APRIL binds to TACI and BCMA (Figure 1) [1••, 2, 3, 4, 5]. In addition, APRIL interacts with proteoglycans, which are structurally unrelated to TNF receptors, and are likely to be the initially unidentified APRIL-specific binding

Two pools of BAFF

There are two distinct pools of BAFF in the mouse. A constitutive pool is produced in fixed amounts by radiation-resistant cells (these are possibly stromal cells from lymphoid organs) and controls the size of the peripheral B cell pool [16••, 17••]. In addition, an accessory cytokine-inducible pool of BAFF is produced locally by cells of myeloid origin, such as monocytes, macrophages, dendritic cells and neutrophils, other fibroblast-like cells or even astrocytes. This cytokine-inducible pool

B cell survival

B-cell development and selection in the bone marrow is independent of BAFF [33, 34]. Only when B cells exit the bone marrow do they become responsive to BAFF survival signals, more precisely as they progress from transitional T1 to transitional T2 stages in the spleen. Survival requires BAFF and BAFF-R, as deletion of either of these genes results in an identical, significant reduction of peripheral B cells that have developed beyond the T1 B cell stage [35]. BAFF is, however, not actively

Concluding remarks

BAFF is a primordial B-cell survival factor that also has additional roles, including T-cell activation; the contribution of APRIL to plasma cell survival, isotype switching and T-independent antibody responses is now relatively well established. Studies published during the past two years have unveiled the roles played by these different receptors, but much remains to be understood concerning the contribution of BAFF and APRIL signaling pathways in mediating these pleiotropic effects. The

Update

The work referred to in the text as (K Ingold et al., unpublished) is now in press [61].

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

I thank Helen Everett for critical reading of the manuscript. This work was supported by grants from the Swiss National Science Foundation.

References (61)

  • T. Hanada et al.

    Suppressor of cytokine signaling-1 is essential for suppressing dendritic cell activation and systemic autoimmunity

    Immunity

    (2003)
  • J. Moreaux et al.

    BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone

    Blood

    (2004)
  • A.J. Novak et al.

    Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival

    Blood

    (2004)
  • J.A. Gross et al.

    TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. Impaired B cell maturation in mice lacking BLyS

    Immunity

    (2001)
  • S. Shulga-Morskaya et al.

    B cell-activating factor belonging to the TNF family acts through separate receptors to support B cell survival and T cell-independent antibody formation

    J Immunol

    (2004)
  • Y. Sasaki et al.

    TNF family member B cell-activating factor (BAFF) receptor-dependent and -independent roles for BAFF in B cell physiology

    J Immunol

    (2004)
  • E. Castigli et al.

    Impaired IgA class switching in APRIL-deficient mice

    Proc Natl Acad Sci USA

    (2004)
  • Q. Ye et al.

    BAFF binding to T cell-expressed BAFF-R costimulates T cell proliferation and alloresponses

    Eur J Immunol

    (2004)
  • E. Varfolomeev et al.

    APRIL-deficient mice have normal immune system development

    Mol Cell Biol

    (2004)
  • I.J. Amanna et al.

    Enforced bcl-xL gene expression restored splenic B lymphocyte development in BAFF-R mutant mice

    J Immunol

    (2003)
  • D.R. Patel et al.

    Engineering an APRIL-specific B cell maturation antigen

    J Biol Chem

    (2004)
  • M. Yan et al.

    Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency

    Curr Biol

    (2001)
  • Y. Liu et al.

    Ligand-receptor binding revealed by the TNF family member TALL-1

    Nature

    (2003)
  • J.L. Bodmer et al.

    The molecular architecture of the TNF superfamily

    Trends Biochem Sci

    (2002)
  • N. Kayagaki et al.

    BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2

    Immunity

    (2002)
  • A.L. Gavin et al.

    DeltaBAFF, an alternate splice isoform that regulates receptor binding and biopresentation of the B cell survival cytokine, BAFF

    J Biol Chem

    (2003)
  • V. Roschke et al.

    BLyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases

    J Immunol

    (2002)
  • Y. Liu et al.

    Crystal structure of sTALL-1 reveals a virus-like assembly of TNF family ligands

    Cell

    (2002)
  • R. Lesley et al.

    Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF

    Immunity

    (2004)
  • M. Krumbholz et al.

    BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma

    J Exp Med

    (2005)
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