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The TNF superfamily ligands BAFF and APRIL and their three receptors BAFFR, BCMA, and TACI comprise a network that is critically involved in the development and function of humoral immunity. Failure of this complex system is associated with autoimmune disease, B lymphocyte tumours, and antibody deficiency. While BAFF:BAFFR interactions control peripheral B cell survival and homeostasis, BCMA function seems limited to the survival of long-lived bone marrow plasma cells. The functional activity of the third receptor TACI is, however, ambiguous: while TACI–/– mice predominantly develop autoimmunity and lymphoproliferation, TACI deficiency in humans primarily manifests itself as an antibody deficiency syndrome. An article in this issue of the European Journal of Immunology demonstrates a negative regulation via TACI in human B cells by using TACI specific antibodies. B cell proliferation, class switch recombination, and Ig production induced by various stimuli were inhibited via TACI. Within the BAFF/APRIL network, the expression of the receptors and ligands is spatially, as well as temporally, highly regulated at various stages of B cell development and function. Defining the exact contribution of TACI stimulation by specific triggers in vitro enables us to better understand the complex, context-dependent responses initiated by TACI in vivo.
a proliferation inducing ligand BAFF: B cell activating factor
B cell maturation protein A
common variable immunodeficiency
transmembrane activator and CAML interactor
The tumor necrosis factor (TNF)-like ligands BAFF (B cell activating factor, synonyms BLyS, THANK, TALL-1, and zTNF4, TNFSF13B) and APRIL (A proliferation inducing ligand, synonyms TALL-2 and TRDL-1, TNFSF13a) and their receptors BCMA (B cell maturation protein A, TNFRSF17), TACI (transmembrane activator and CAML Interactor, TNFRSF13B) and BAFFR (BAFF receptor, TNFRSF13C) are members of a superfamily of genes which transduce key signals to regulate B cell homeostasis, differentiation and function.
Several features are characteristic for all three BAFF/APRIL receptors: (i) all are Type III transmembrane proteins, lacking the signal-peptide as found in the Type I transmembrane protein family, which most TNFR superfamily members belong to; (ii) they all contain cysteine-rich extracellular domains characteristic of members of the TNFR superfamily; and (iii) their expression is restricted to lymphocytes.
Other features, unique for each single receptor, define its specific role in the receptor network. For example, BAFFR exclusively binds BAFF and is highly expressed on all peripheral B cells 1. The BAFF:BAFFR interaction is crucial for the survival of all peripheral B cell subsets as evidenced by severe B cell lymphopenia and humoral immunodeficiency in both BAFF- and BAFFR-deficient mouse strains 2, 3. In contrast, BCMA expression is highly restricted to the end stages of B cell differentiation 4, 5 and seems to be essential for the survival of long-lived bone marrow plasma cells 6.
TACI differs by some unique structural features from BCMA and BAFFR. TACI has two additional 5′ exons allowing the receptor to be expressed as two splice variants containing either one or two cysteine-rich extracellular domains, of which only one seems to be functionally relevant 7. TACI is able to bind APRIL and BAFF equally with high affinity 7, and serves as the only receptor for BAFF/APRIL heterotrimers 8. Additionally, both APRIL and its receptor TACI were recently shown to be capable of interacting with proteoglycans 9, 10. Finally, TACI was originally identified as a CAML interacting receptor 11 and thus is able to signal both via the NFκb and NFAT/AP-1 signalling pathways.
TACI expression varies on distinct B cell subpopulations. In humans, a pronounced expression is found on marginal zone B cells and on CD27+ memory B cell subsets 1, 4, 5. In addition, TACI expression is strongly up-regulated after B cell stimulation 12, 13. Apart from these particular features of TACI, there are ambiguous biological activities in the humoral immunity of both mice and humans attributed to this receptor, which are summarized in Fig. 1.
Figure 1. Summary of TACI functions observed in humans and in mice in vivo and in vitro. TI, T cell independent; CSR, class switch recombination; CVID, common variable immunodeficiency; DC, dendritic cell.
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Three tnfrs13b–/– mouse strains have been reported, showing a notable diversity in their immunological phenotypes 14–16. The tnfrs13b–/– mouse model by von Bülow et al. showed that TACI is indispensable for the generation and maintenance of T cell-independent Type II responses directed against polysaccharide antigens of encapsulated bacteria like Streptococcus pneumoniae. B cell numbers were elevated, but B cells developed normally. A normal architecture of secondary lymphoid organs with intact germinal centers was present reflecting the unimpaired T cell-dependent humoral responses in these mice 14. The TACI knockout mice by Yan et al.15 confirmed the expansion of peripheral B cells and the impaired T cell-independent Type II response; however, the authors observed an altered splenic architecture with prominent germinal centers and an increased cellularity of B cell follicles. The B cells were hyperresponsive to mitogenic stimuli with respect to proliferation and immunoglobulin (Ig) production indicating that TACI may serve as a negative regulator 15. This notion was further supported by a third report on a tnfrs13b–/– mouse model in 2003 by Seshasayee et al.16. Their tnfrs13b–/– mouse strain spontaneously developed a fatal systemic lupus erythematosus-like disorder characterized by autoimmune nephritis. Up to 15% of these TACI–/– mice spontaneously developed lymphoma. Seshasayee et al. 16 also reproduced the inhibitory function of TACI in murine B cell responses in vitro using agonistic anti-murine TACI antibodies. In summary, the knockout studies in mice suggested a predominant inhibitory role for TACI in immune responses.
In contrast to these findings other in vitro studies established APRIL and BAFF as T cell independent inducers of class switch recombination in B cells 17, 18. Murine naïve B cells secrete the switched isotypes IgG1 and IgA in response to APRIL and BAFF without additional stimuli and IgE with the help of IL-4. This process was mediated through both BAFFR and TACI 18. In particular, the APRIL:TACI interaction seems to be critical for the induction of IgA as APRIL–/– mice show a selective deficiency of this isotype and BAFFR is unable to bind APRIL 19. In human B cells, BAFF and APRIL induce class switching towards IgG and IgA in the presence of IL-10 or TGF-β and IgE in the presence of IL-4 17.
Further evidence that TACI positively regulates terminal B cell differentiation came from the discovery that mutations in TNFRSF13b/TACI were associated with common variable immunodeficiency (CVID) in humans 20, 21. In contrast to the B cell phenotype in TACI-deficient mice, B cell numbers in human TACI deficiency tend to be normal or slightly reduced, with a variable reduction of CD27+ memory B cells in most of the patients; however, most of these analyses are limited to the peripheral blood compartment and an enlargement of the secondary lymphoid organs is frequently present in TACI-deficient humans 20. None of the patients with a mutation in TACI developed any clinical features of systemic lupus erythematosus. The observed autoimmune phenomena or disease in up to 30% of patients with TACI deficiency may or may not be directly related to mutations in TNFRSF13b because autoimmune phenomena represent a common complication of CVID patients in general. Antibody responses after vaccination with pneumovax were selectively impaired in TACI-deficient humans 21, which concurs with the observations in mice 14; however, in humans with TACI deficiency the hypogammaglobulinemia affected all the Ig isotypes resulting in nearly agammaglobulinemic states in some patients 20. Thus, TACI deficiency primarily manifests itself as an immunodeficiency in humans.
There are several possible explanations for the differences between the murine and human TACI–/– phenotype: (i) the uniform, inbred genetic background of the mice does not represent the human outbred population; (ii) most of the mutations in humans do not lead to a complete loss of the TACI protein which could allow the receptor to be partially functional; (iii) most of the mutations in TNFRSF13b are heterozygous, not 100% penetrant, and vary in their expressivity; thus, additional genetic factors may contribute to the development of a full-blown immunodeficiency; and (iv) the TACI-deficient mouse strains were held under pathogen free conditions; the clinical picture of CVID, however, often evolves after a year-long struggle between pathogens and an immunocompromised host.
The work of Sakurai et al.13 in this issue of the Journal resolves some of the ambiguity related to the biological functions of TACI by using agonistic TACI-specific antibodies. This approach reduces the more complex physiologic situation where multiple simultaneous or successive interactions may occur between TACI, its co-receptors and ligands. In their work, Sakurai et al.13 demonstrate for the first time a negative regulation of human B cell responses in vitro by triggering TACI with agonistic TACI-specific antibodies. These authors also provide evidence that the inhibitory effect of TACI on human B cells is exerted by the blockade of key events in terminal B cell differentiation rather than the induction of apoptosis, which was suggested as the mechanistic explanation for inhibitory effects via TACI in mice 16. Another important insight is that TACI expression is dependent on previous activation of B cells via CD40, BAFFR, or surface IgM, thereby licensing TACI as a terminator for B cell function. This partially resembles the expression kinetics and function of CTLA-4 on T cells.
In conclusion, there is now evidence for positive and negative regulatory effects of TACI stimulation both in the murine and human system; however, the result of TACI engagement by its ligands in vivo will always be context dependent. It may further depend on the status of differentiation and activation of the triggered B cell. Thus, TACI may serve more as a rheostat than as a simple on/off switch in humoral immune responses. To identify the precise conditions and signalling pathways which determine the outcome of TACI engagement remains the challenge for future research.