Elsevier

Seminars in Immunology

Volume 18, Issue 5, October 2006, Pages 284-289
Seminars in Immunology

Review
The role of the BAFF/APRIL system on T cell function

https://doi.org/10.1016/j.smim.2006.04.005Get rights and content

Abstract

BAFF is a key factor controlling B cell survival and maturation and its over-expression promotes B cell-mediated autoimmune disorders and participates in the progression of B cell lymphomas. Yet, BAFF and a related ligand APRIL are expressed by T lymphocytes and modulate their functions. BAFF and APRIL promote T cell activation and survival. BAFF over-expression in transgenic (Tg) mice enhances T helper 1 (Thl)-driven delayed-type hypersensitivity (DTH), but inhibits T helper 2 (Th2) cell-mediated allergic airway inflammation in mice. Some of these effects are also dependent on BAFF-induced modification of the B cell compartment. Therefore, direct BAFF/APRIL signalling in T cells and/or T cell modulation in response to a BAFF-modified B cell compartment may play an important role in inflammation and immunomodulation.

Introduction

BAFF (B cell activating factor belonging to the tumor necrosis factor (TNF) family also termed BLyS, TALL-1, zTNF-4, THANK, and TNFSF13) is a homotrimer, member of the TNF superfamily expressed on the cell surface or cleaved and secreted [1], [2]. Another related TNF ligand, A proliferation-inducing ligand (APRIL, also known as TALL-2, TRDL1 or TNFSF13)[3] shares two receptors with BAFF, transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (TACI) and B-cell maturation antigen (BCMA, TNFSFR17) [1], [2]. In contrast to BAFF, APRIL is cleaved from the Golgi and only exists as a secreted soluble ligand [4]. BAFF also specifically binds to a third receptor, BAFF receptor (BAFF-R, also known as BR3) [1], [2]. Interestingly, APRIL binds to proteoglycan structures on the cell surface, however, it is unclear whether this interaction leads to physiological signalling or helps concentrating APRIL on the cell surface for better cross-linking of the receptors, a feature essential for efficient signalling [5], [6]. APRIL/BAFF heterotrimers have been detected in the serum of patients with rheumatic disease and appear to bind only to TACI [7]. In addition, a spliced variant form of BAFF was identified which can form non-cleavable and functionally inactive homotrimers with normal BAFF subunits [8], [9]. Finally, an alternative splicing event in the TWEAK/APRIL locus leads to the formation of a TWEAK/APRIL hybrid ligand named TWE-PRIL, composed of the APRIL extracellular domain and TWEAK transmembrane portion. This ligand is biologically active possibly via TACI, BCMA and, possibly proteoglycan structures [10].

The discovery of BAFF has shed new light on the importance of finely tuned B cell survival for B cell tolerance during B cell maturation and activation [1], [2], [11], [12], [13]. BAFF particularly supports survival of splenic immature transitional and mature B cells. Thus, maturation beyond the immature transitional type 1 (T1) stage is impaired in BAFF-deficient mice (BAFF−/−) [13], [14], [15]. Mice over-expressing BAFF develop autoimmune disorders similar to systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) in humans, possibly as the result of improper B cell survival, predominantly affecting the maturing splenic transitional type 2 (T2) and the marginal zone (MZ B) cell populations (reviewed in refs. [13], [14], [16], [17], [18], [19]). Indeed, when the hen egg lysozyme (HEL) transgenic system was used to assess the effect of excess BAFF production on B cell tolerance, results revealed a BAFF-induced escape of low/intermediate affinity self-reactive B cells, in particular MZ B cells [20]. BAFF-induced autoimmunity in BAFF transgenic (Tg) mice appears to be highly dependent on B cells and possibly the production of autoantibodies [21]. Previous studies in BAFF Tg mice lacking TNF and, therefore, unable to mount proper T-dependent immune response and form germinal centres to improve antibody affinity, developed autoimmune symptoms as severe as those seen in the original BAFF Tg mice [21]. This work revealed that the role of T cells in BAFF-induced autoimmunity was either minimal or un-conventional. However, the status of the T cell compartment in BAFF Tg mice is clearly altered with the expansion of the effector T cell compartment [16]. This unusual aspect prompted the study of the exact role the BAFF/APRIL system on T cell functions. In this review, we have collated all recent findings and attempted to establish the place of T cells in BAFF/APRIL-mediated biological activities.

Section snippets

Expression of BAFF, APRIL and receptors on T cells

Expression of BAFF by T cells has been a controversial issue for some time with groups clearly detecting expression, particularly in activated T cells [22], [23], [24], [25], while several other studies were unable to show significant BAFF production [26], [27], [28], [29]. In many reports, BAFF mRNA expression by T cells is rather weak compared to that of dendritic cells [24], which was also reflected at the protein level [25]. As activated T cells also express APRIL [23], [30], the

Direct modulation of T cell responses by BAFF and APRIL in vitro

BAFF acts directly on T cells to enhance human T cell response to anti-CD3 activation [24], [41]. This effect was shown to be a true co-stimulatory effect rather than increased basal T cell survival. Same results were obtained with mouse splenic T cells stimulated with anti-CD3 mAb plus BAFF [24]. Interestingly, this effect was only obtained when BAFF was immobilized but not when used in soluble form [24], [41], [42], suggesting that interaction between BAFF and its receptor on T cells required

Modulation of T cell function in BAFF, APRIL and receptor mutant or transgenic mice (Table 1)

In vitro studies described above have confirmed the role of BAFF as a co-stimulating/survival factor of activated T cells. However, the physiological importance of BAFF function in T cells in vivo remains to be established. We have shown that Thl-mediated DTH was mostly normal in BAFF−/− mice, suggesting that BAFF is not required for T cell activation and Thl differentiation in vivo. As mentioned above, we have shown that anti-CD28 antibody co-stimulation can compensate for the lack of

Conclusions and perspective

While the role of BAFF in B cell biology is dominant, it is now clear that, either directly or indirectly, this cytokine can modulate T cell function in vitro and in vivo. Recent data showing a protective effect of BAFF production against T cell-mediated inflammation, combined with the observation of BAFF-R expression on most regulatory T cells, is particularly interesting as further experiments may uncover useful new mechanisms for the regulation of T cells and possibly new options for

Acknowledgments

We would like to thank Shane Grey, Marcel Batten, Lai Guan Ng, Andrew Sutherland, Ian Sutton, Frederic Sierro, Stuart Tangye and Pablo Silveira for critical reading of the manuscript and unpublished observations. Fabienne Mackay is a Wellcome Trust senior research fellow and is also supported by the National Health Medical and Research Council in Australia and the New South Wales Lupus association.

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