Transmembrane Activator And Calcium Modulator And Cyclophilin Ligand Research Articles

TACI Constrains TH17 Pathogenicity and Protects against Gut Inflammation.

SummaryTACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) plays critical roles in B cells by promoting immunoglobulin class switching and plasma cell survival. However, its expression and function in T cells remain controversial. We show here that TACI expression can be strongly induced in murine CD4+ T cells in vitro by cytokines responsible for TH17 but not TH1 or TH2 differentiation. Frequencies and numbers of TH17 cells were elevated in TACI−/− compared with wild-type mice as well as among TACI−/− versus wild-type CD4+ T cells in mixed bone marrow chimeras, arguing for a T cell-intrinsic effect in the contribution of TACI deficiency to TH17 cell accumulation. TACI−/− mice were more susceptible to severe colitis induced by dextran sodium sulfate or adoptive T cell transfer, suggesting that TACI negatively regulates TH17 function and limits intestinal inflammation in a cell-autonomous manner. Finally, transcriptomic and biochemical analyses revealed that TACI−/− CD4+ T cells exhibited enhanced activation of TH17-promoting transcription factors NFAT, IRF4, c-MAF, and JUNB. Taken together, these findings reveal an important role of TACI in constraining TH17 pathogenicity and protecting against gut disease.

An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma

AbstractB-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM), but expression is variable, and early reports of BCMA targeting chimeric antigen receptors (CARs) suggest antigen downregulation at relapse. Dual-antigen targeting increases targetable tumor antigens and reduces the risk of antigen-negative disease escape. “A proliferation-inducing ligand” (APRIL) is a natural high-affinity ligand for BCMA and transmembrane activator and calcium-modulator and cyclophilin ligand (TACI). We quantified surface tumor expression of BCMA and TACI on primary MM cells (n = 50). All cases tested expressed BCMA, and 39 (78%) of them also expressed TACI. We engineered a third-generation APRIL-based CAR (ACAR), which killed targets expressing either BCMA or TACI (P < .01 and P < .05, respectively, cf. control, effector-to-target [E:T] ratio 16:1). We confirmed cytolysis at antigen levels similar to those on primary MM, at low E:T ratios (56.2% ± 3.9% killing of MM.1s at 48 h, E:T ratio 1:32; P < .01) and of primary MM cells (72.9% ± 12.2% killing at 3 days, E:T ratio 1:1; P < .05, n = 5). Demonstrating tumor control in the absence of BCMA, we maintained cytolysis of primary tumor expressing both BCMA and TACI in the presence of a BCMA-targeting antibody. Furthermore, using an intramedullary myeloma model, ACAR T cells caused regression of an established tumor within 2 days. Finally, in an in vivo model of tumor escape, there was complete ACAR-mediated tumor clearance of BCMA+TACI− and BCMA−TACI+ cells, and a single-chain variable fragment CAR targeting BCMA alone resulted in outgrowth of a BCMA-negative tumor. These results support the clinical potential of this approach.

Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation

We have assessed the role of B lymphocyte stimulator (BLyS) and its receptors in the germinal center (GC) reaction and affinity maturation. Despite ample BLyS retention on B cells in follicular (FO) regions, the GC microenvironment lacks substantial BLyS. This reflects IL-21-mediated down-regulation of the BLyS receptor TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) on GC B cells, thus limiting their capacity for BLyS binding and retention. Within the GC, FO helper T cells (TFH cells) provide a local source of BLyS. Whereas T cell-derived BLyS is dispensable for normal GC cellularity and somatic hypermutation, it is required for the efficient selection of high affinity GC B cell clones. These findings suggest that during affinity maturation, high affinity clones rely on TFH-derived BLyS for their persistence.

BAFF maintains T-cell survival by inducing OPN expression in B cells

Dysregulation of T-cell survival and apoptosis is the common cause of autoimmune diseases such as multiple sclerosis (MS). However, the factors inducing imbalance of T-cell survival and apoptosis in MS remains unclear. Here, we show that the resistance to apoptosis was associated with high levels of B-cell activating factor (BAFF). Blockade of BAFF with TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor)-IgG significantly reduced T-cell survival in myelin oligodendroglia glycoprotein (MOG)-induced chronic experimental allergic encephalitis (EAE). Furthermore, BAFF induced anti-apoptotic molecule Bcl2 expression in T cells by up-regulating osteopontin (OPN) secretion from B cells. BAFF mainly induced OPN expression in splenic CD21−CD23+ B cells via a NF-kB dependent signaling pathway. In addition, we found that BAFF and OPN levels were increased in MS patients similar to the results obtained from our mice research. The study suggests that BAFF regulates T-cell survival by inducing OPN secretion in B cells in autoimmune diseases.

Identify the key amino acid of BAFF binding with TACI

B-cell activating factor (BAFF) has been used as a therapeutic target. To develop BAFF-specific small molecular inhibitors, it is necessary to know the key amino acid in the BAFF binding with its receptor. The key binding amino acid of BAFF interacting with its receptor TACI (trans-membrane activator and calcium modulator and cyclophilin ligand interactor) was analyzed based on the computer-guided molecular modeling method. According to theoretical prediction, a series of key amino acid mutants of BAFF, including M204 (Lys204 to Ala), M208 (Met208 to Ala), M209 (Gly209 to Ala), M210 (His210 to Ala), M234 (Gln234 to Ala), M236 (Met236 to Ala), and M237 (Pro237 to Ala) were designed and evaluated with biological experiments. The results show that M208, M209, M236, and M237 of BAFF were the key amino acids and in accord with the theoretical results. The results highlight clues for the further development of BAFF-specific small molecular inhibitors.

Rare mutations in TNFRSF13B increase the risk of asthma symptoms in Swedish children

TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) mutations seem to be associated with autoimmunity and common variable immunodeficiency in humans. Because of its role in immune responses, we investigated the association between TACI mutations and infection proneness/asthma symptoms in children. A total of 2372 children were genotyped for TACI mutations (I87N, C104R, S144X, A181E, R202H and ins204A). Serum IgA, IgG and specific IgE levels were determined in children with mutations. Data on parentally reported allergic diseases and infections were collected. In all, 55 individuals with TACI mutations were identified. Children with TACI mutations had a 2-fold increased risk of wheeze at 2 and 4 years of age and a 2.5-fold increased risk of asthma was seen at 4 years of age. None of the children with mutations suffered from IgA deficiency (<0.07 g l(-1)). No significant differences in serum IgG levels or specific IgE were found. Common variants in asthma susceptibility genes may account for up to 40% of cases of childhood-onset asthma, indicating a high contribution, compared with other common disorders. The role of rare variants/mutations in the pathogenesis of asthma is less clear. We conclude that mutations in TACI are the contributing factors for asthma symptoms in Swedish children, although the mechanisms still remain elusive.

Innate immune defects correlate with failure of antibody responses to H1N1/09 vaccine in HIV-infected patients

Mechanisms underlying the failure of influenza vaccine-induced antibody responses in HIV-infected persons are poorly understood. To investigate innate immune factors regulating B-cell function in HIV-infected persons and to correlate them with serologic responses to H1N1/09 vaccine. We evaluated immunologic characteristics of 17 HIV-infected patients and 8 healthy controls (HCs) at 0, 7, and 28 days (designated T0, T1, and T2) following a single 15-μg dose of nonadjuvanted H1N1/09 influenza vaccine by using flow cytometry, ELISpot, and ELISA. All HCs and 9 patients (53%) seroconverted with >1:40 hemagglutination inhibition antibody titer at T2. In vaccine responders and HCs, serum levels of BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand) increased from T0 to T2 in conjunction with increases in frequencies of memory B cells. Concurrently, receptors for these factors showed changes, with increases in expression of TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and decreases in BAFF receptor in memory B cells. IL-2 secreting cells and IgG antibody-secreting cells increased at T2 in vaccine responders and HCs in exvivo H1N1 antigen-stimulated cultures. These immunologic responses were not evident at T1 and were deficient in vaccine nonresponder patients at T2. At T0, vaccine nonresponders had lower frequencies of BAFF receptor and TACI-expressing memory B cells than did responders. Impaired memory B-cell responses, deficiencies in serum BAFF and APRIL, and alterations in their receptors on B cells were associated with failure of H1N1/09 influenza vaccine responses among virologically controlled HIV-infected patients.

B‐lymphocyte biology

B‐lymphocyte biology

Defective B-cell Response to Toll-like Receptor-9 Ligands in Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a primary immune defect typified by low levels of IgG, IgM, and IgA and poor antibody responses to carbohydrate and protein antigens that leads to increased risk of sinopulmonary infections [1]. The organisms responsible for these infections are typically encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae [2]. Effective treatment is replacement intravenous IgG [1]. Impaired antibody responses in CVID have been explained for some CVID patients by recent discoveries of genetic mutations and polymorphisms such as TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), CD19, and ICOS (inducible co-stimulator). However, these account for only 10% of CVID patients. For the remaining CVID patients, a molecular defect has not been identified [3, 4]. Toll-like receptors (TLRs) are pathogen-recognition receptors that are crucial for microbial elimination, whether through recruitment of phagocytes or activation of dendritic cells [5]. B cells also use TLRs as a means of activation and differentiation [3]. Of the 10 TLRs expressed in humans, B cells use TLR1, TLR2, TLR6, TLR7, TLR9, and TLR10. Of these, TLR7 and TLR9 are expressed in the endosomal compartment, whereas the other TLRs are expressed on the cell surface. TLR7 and TLR9 are expressed in low levels by naive B cells, and B-cell receptor (BCR) cross-linking leads to rapid upregulation of their expression [6]. Ligation of TLR7 and TLR9 can provide a signal for differentiation of B cells after antigenic stimulation through the BCR [7]. The ligand for TLR7 includes single-stranded RNA, and the ligand for TLR9 is CpG-ODN (CpG motifs in DNA oligodeoxynucleotides), which is more prevalent in prokaryotes. Defects in TLR7 and TLR9 have been reported for the B cells of CVID patients [3].

BAFF: a local and systemic target in autoimmune diseases

BAFF (B lymphocyte activating factor of the tumour necrosis factor family) is a vital homeostatic cytokine for B cells that helps regulate both innate and adaptive immune responses. Increased serum levels of BAFF are found in a number of different autoimmune diseases, and BAFF is found in inflammatory sites in which there is lymphoid neogenesis. BAFF antagonism has been used in several autoimmune disease models, resulting in B cell depletion, decreased activation of T cells and dendritic cells (DC) and a reduction in the overall inflammatory burden. BAFF, through its interaction with BAFF-R, is required for survival of late transitional, marginal zone and mature naive B cells, all of which are depleted by BAFF blockade. Through their interactions with TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B cell maturation protein), BAFF and its homologue APRIL (a proliferation-inducing ligand), support the survival of at least some subsets of plasma cells; blockade of both cytokines results in a decrease in serum levels of immunoglobulin (Ig)G. In contrast, neither BAFF nor APRIL is required for the survival or reactivation of memory B cells or B1 cells. BAFF also helps DC maturation and interleukin (IL)-6 release and is required for proper formation of a follicular dendritic cell (FDC) network within germinal centres, although not for B cell affinity maturation. The clinical efficacy of BAFF blockade in animal models of autoimmunity may be caused both by the decline in the number of inflammatory cells and by the inhibition of DC maturation within target organs. Blockade of BAFF and its homologue APRIL are being explored for human use; several Phase I and II clinical trials of BAFF inhibitors for autoimmunity have been completed and Phase III trials are in progress.

Murine Model of the Human TACI Mutation A181E

TACI (transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor), is a TNF receptor (TNFR) family member expressed on B cells and is a receptor for BAFF and APRIL. TACI is mutated in ∼10% of CVID patients. A181E mutations in particular have been significantly associated with this disease. TACI-/- mice have decreased serum IgA levels and impaired response to the type II T independent (TI) antigens TNP-Ficoll and pneumococcal polysaccharides. To understand the effect of the human TACI A181E mutation on B cell development and function we generated TACI-/- mice that express a murine TACI A144E transgene, the equivalent to human TACI A181E.

Mutations in TNFRSF13B Encoding TACI Are Associated With Common Variable Immunodeficiency in Humans

&amp;gt;Purpose of the Studies.To search for mutations of TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor; also TNFRSF13B) in patients with common variable immunodeficiency (CVID) and immunoglobulin A deficiency (IGAD).Study Populations.Salzer et al screened 162 unrelated individuals with CVID. Castigli et al studied 19 unrelated individuals with CVID and 16 with IGAD. Healthy individuals (100 and 50, respectively) served as controls.Methods.Genomic DNA from patients was subjected to reverse transcription and polymerase chain reaction sequencing analysis of the 5 exons of the gene encoding TACI. Binding of mutant TACI to ligands and stimulation of immunoglobulin production in vitro with TACI agonists in patients was also studied.Results.Salzer et al identified 13 individuals with CVID who had mutations in TACI. Castigli et al identified 4 individuals with CVID and 1 with IGAD and TACI mutations. None of the 150 controls studied had any of the identified TACI mutations. Interestingly, TACI mutations could cause disease in both the heterozygous and homozygous conditions. Patients’ cells had diminished binding to TACI ligands and showed diminished responses (immunoglobulin production) to TACI agonists in vitro. The clinical characteristics of the patients included hypogammaglobulinemia and impaired antibody responses, recurrent bacterial sinopulmonary infections, autoimmune disease (anemia, thyroiditis, positive antinuclear antibody), lymphoproliferative disease, and malignancy (B-cell lymphoma, gastric carcinoma).Conclusions.Approximately 8% to 20% of patients with severe combined immunodeficiency or IGAD may have heterozygous or homozygous mutation in TACI. This genetic alteration should be sought in patients with these disorders.Reviewer Comments.CVID and IGAD are among the most prevalent humoral immunodeficiencies at all ages. These studies represent important descriptions of defined mutations in patients with CVID and IGAD occurring in a significant fraction of these patients in 2 relatively genetically disparate populations. The ability to clearly define the underlying cause of disease in these patients will immediately lead to greater accuracy and confidence in diagnosis, earlier and more aggressive therapy, and, hopefully, improved outcomes.

The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature

AbstractB-cell activating factor (BAF1111116) and a proliferation-inducing ligand (APRIL) have been shown to promote multiple myeloma (MM) cell growth. We show that the main site of production for BAFF and APRIL is the bone marrow (BM) environment, and that production is mainly by monocytes and neutrophils. In addition, osteoclasts produce very high levels of APRIL, unlike BM stromal cells. Myeloma cells (MMCs) express TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), the receptor of BAFF/APRIL, at varying levels. TACI expression is a good indicator of a BAFF-binding receptor. Expression data of purified MMCs from 65 newly diagnosed patients have been generated using Affymetrix microarrays and were analyzed by supervised clustering of groups with higher (TACIhi) versus lower (TACIlo) TACI expression levels. Patients in the TACIlo group had clinical parameters associated with bad prognosis. A set of 659 genes was differentially expressed between TACIhi and TACIlo MMCs. This set makes it possible to efficiently classify TACIhi and TACIlo MMCs in an independent cohort of 40 patients. TACIhi MMCs displayed a mature plasma cell gene signature, indicating dependence on the BM environment. In contrast, the TACIlo group had a gene signature of plasmablasts, suggesting an attenuated dependence on the BM environment. Taken together, our findings suggest using gene expression profiling to identify the group of patients who might benefit most from treatment with BAFF/APRIL inhibitors.