The role of APRIL and BAFF in lymphocyte activation
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.
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