TACI, an enigmatic BAFF/APRIL receptor, with new unappreciated biochemical and biological properties
Introduction
B cell Activating Factor from the TNF family (BAFF, also termed BLyS, and TNFSF13b) has been identified almost a decade ago and extensive work on this cytokine has led to important new discoveries defining the mechanisms governing B cell survival, maturation and tolerance [1], [2], [3], [4]. The development of several mutant mouse models in this system has established that interaction of BAFF with its BAFF receptor (BAFF-R, BR3, TNFRSF13C) is the driver of B cell survival and maturation [1], [2], [3], [4]. In addition, major progresses have been made identifying the signalling events associated with BAFF-R-mediated B cell survival [1], [2], [3], [4]. BAFF binds to two other receptors, transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (TACI, TNFRSF13B) and B cell maturation antigen (BCMA, TNFRSF17) also recognizing another TNF-like ligand: A proliferation-inducing ligand (APRIL, TNFSF13) [1], [2], [3], [4] (Fig. 1). These two receptors have more restricted functions compared to BAFF-R, with TACI controlling T cell-independent B cell antibody responses, isotype switching and B cell homeostasis, whereas the function of BCMA is mostly limited to the survival of plasma cells residing in the bone marrow [1], [2], [3], [4].
Excessive BAFF production in BAFF transgenic (Tg) mice leads to the development of severe autoimmune disorders similar to systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) [5], [6]. Moreover, elevated serum BAFF levels in humans also correlate with the development of several autoimmune conditions [7]. Since ablation of BAFF-R prevents B cell maturation [1], [2], [3], [4], it has always been difficult to properly address the role of this receptor in mature B cell tolerance, but it was postulated that excessive BAFF favoured survival and escape of auto-reactive B cells during B cell maturation. How TACI provides positive signals driving T-independent B cell response [8], [9] and survival of activated B cells and plasmablast [10], but also delivers negative signals suppressing B cell activation [8], [9], [11] has been a long-standing mystery. In this review, we will detail the latest exciting and intriguing aspects of the biology of TACI, such as the specific ligand requirements necessary to trigger signals through this receptor, its role in B cell function, macrophages, autoimmunity and cancer, its relationship with the innate activation mechanisms as well as its emerging implication in human immunodeficiency.
Section snippets
General ligand–receptor interactions
BAFF and APRIL are membrane-bound ligands that can be processed to soluble forms by proteolytic cleavage [12], [13]. Soluble forms of these ligands contain the C-terminal, homotrimeric TNF-homology domain that mediates binding to receptors. BAFF contains a 10 amino acid-long loop that protrudes out of this domain and that serves to assemble twenty soluble BAFF 3-mers into a virus-like particle [14]. In contrast to BAFF, APRIL forms trimers but not higher order structures. It however contains a
TACI expression
TACI is mainly expressed on B cells, especially on activated B cells, but early data suggested that TACI was also expressed on a subset of T cells [49] and two separate studies have confirmed a strong TACI signal not only in the spleen but also in the thymus by Northern blot analysis [49], [50]. However, development of mouse and human TACI-specific monoclonal antibodies failed to confirm TACI expression on the surface of both mouse and human T cells [51], [52]. This does not exclude a possible
Autoimmunity in TACI−/− mice versus BAFF Tg mice
Excessive production of BAFF triggers SLE-like autoimmunity in mice [5]. Similar autoimmune disorders develop in TACI−/− mice, but with some noticeable differences [11]. BAFF is critical at the immature transitional stage during splenic B cell maturation and allows type 1 to type 2 (T1/T2) transition by providing survival signals [72], [77], [78]. As a result, BAFF over-expression in BAFF Tg mice does not affect the number of T1 B cells but increases that of B cells beyond the T1 B cell stage,
Expression on human cells and tumours
BAFF-R is widely expressed on human B cell subsets such as naïve, memory B cells and plasma cells (PCs) [51], but not on PCs from the bone marrow (BM) and spleen [94], [95]. BCMA is expressed on PCs from tonsils, spleen and BM [94], [95], but also on tonsillar memory B cells and in germinal center (GC) B cells, the latter being TACI-negative and BAFF-Rlow [51], [94]. TACI is expressed in CD27+ memory B cells, tonsillar and BM PCs, in a subpopulation of activated CD27−, non-GC cells [51], [53],
Conclusions and remaining questions
The past 3 years have brought some important new information about the role of TACI in the BAFF/APRIL system. Regulation of TACI expression is intimately linked to activation of innate receptors on B cells such as TLR [10], [53], [54], [55], and this may explain the critical role of TACI as a driver of T cell-independent immune responses [8], [9]. We now know that autoimmunity in BAFF Tg mice is a T cell-independent process [53], and current data suggest that TACI may play a greater role in
Acknowledgements
FM is supported by the National Health and Medical Research Council, the NSW Lupus association and the Rebecca Cooper foundation. PS is supported by grants of the Swiss National Research Foundation.
Prof. Fabienne Mackay is the Director of the Autoimmunity Research Unit at the Garvan Institute of Medical Research in Sydney, and full professor at the Faculty of Medicine, University of New South Wales. Prof. Mackay obtained her PhD in 1994 at the Louis Pasteur University in Strasbourg, France. In 1994, she joined BiogenIdec Inc. in Boston where she dissected the role of lymphotoxin-alpha/beta in autoimmunity and cancer. This work led to many patents and one new treatment currently tested in
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Cited by (0)
Prof. Fabienne Mackay is the Director of the Autoimmunity Research Unit at the Garvan Institute of Medical Research in Sydney, and full professor at the Faculty of Medicine, University of New South Wales. Prof. Mackay obtained her PhD in 1994 at the Louis Pasteur University in Strasbourg, France. In 1994, she joined BiogenIdec Inc. in Boston where she dissected the role of lymphotoxin-alpha/beta in autoimmunity and cancer. This work led to many patents and one new treatment currently tested in the clinic. In 1998, her lab discovered the TNF-like ligand BAFF and its role in B cell-driven autoimmunity. In 2000, she joined the Garvan Institute in Sydney as a Wellcome Trust senior research fellow holding a National Health and Medical Research Council (NHMRC) program grant. Professor Mackay is a member of several editorial boards. Her lab at Garvan discovered the role of BAFF as a key B cell survival factor. She has authored more than 70 articles/reviews/book chapters and she is a consultant for several biotech and pharmaceutical groups. Her group has very recently discovered a new form of lupus and a new gene responsible for the development of heart valves and angiogenesis in cancer.
Pascal Schneider studied biochemistry earning his PhD in 1992 at the University of Lausanne, in the group of J. Mauël. He performed a post-doc with MAJ Ferguson at the University of Dundee, Scotland, and then joined the research group of professor Jurg Tschopp in the Department of Biochemistry at the University of Lausanne, where he was appointed assistant professor in 2002. Ligands and receptors of the TNF family are his major research interest.