T-dependent Research Articles

Exercise improves intestinal IgA production by T-dependent cell pathway in adults but not in aged mice.

Hypermutated high-affinity immunoglobulin A (IgA), neutralizes toxins and drives the diversification of bacteria communities to maintain intestinal homeostasis although the mechanism underlies the impact of moderate aerobic exercise (MAE) on the IgA-generation via T-dependent (TD) is not fully know. Therefore, the aim of this study was to determine the effect of long-time MAE on the production of IgA through the TD pathway in Peyer´s patches of the small intestine from aged mice. MAE protocol consisted of twenty 3-month-old (young) BALB/c mice running in an endless band at 0° inclination and a speed of 10 m/h for 5 days a week and resting 2 days on the weekend until reaching 6-month-old (adulthood, n=10) or 24-month-old (aging, n=10). Groups of young, adult, or elderly mice were included as sedentary controls (n=10/per group). At 6 or 24 months old, all were sacrificed, and small intestine samples were dissected to prepare intestinal lavages for IgA quantitation by ELISA and to obtain suspensions from Peyer´s patches (PP) and lamina propria (LP) cells for analysis of T, B, and plasma cell subpopulations by flow cytometry and mRNA analysis expression by RT-qPCR of molecular factors related to differentiation of B cells to IgA+ plasma cells, class switch recombination, and IgA-synthesis. Statistical analysis was computed with two-way ANOVA (factor A=age, factor B=group) and p<0.05 was considered for statistically significant differences. Compared to age-matched sedentary control, in exercised elderly mice, parameters were either increased (IgA concentration, IL-21, IL-10 and RDH mRNA expression), decreased (α-chain mRNA, B cells, mIgA+ B cells, mIgM+ B cells and IL-4 mRNA) or unchanged (PP mIgA+ plasmablasts and LP cyt-IgA+ plasma cells). Regarding the exercised adult mice, they showed an up-modulation of IgA-concentration, mRNA expression IL-21, IL-10, and RDH and cells (PP B and T cells, mIgM+ plasmablasts and LP cyt-IgA+plasma cells). Our findings suggest that MAE restored the IgA production in adult mice via the TD cell pathway but does not in aged mice. Other studies are necessary to know in more detail the impact of long-time MAE on the TD pathway to produce IgA in aging.

TRAF6 and TRAF2/3 Binding Motifs in CD40 Differentially Regulate B Cell Function in T-Dependent Antibody Responses and Dendritic Cell Function in Experimental Autoimmune Encephalomyelitis.

Expression of the costimulatory molecule CD40 on both B cells and dendritic cells (DCs) is required for induction of experimental autoimmune encephalomyelitis (EAE), and cell-autonomous CD40 expression on B cells is required for primary T-dependent (TD) Ab responses. We now ask whether the function of CD40 expressed by different cell types in these responses is mediated by the same or different cytoplasmic domains. CD40 has been reported to possess multiple cytoplasmic domains, including distinct TRAF6 and TRAF2/3 binding motifs. To elucidate the invivo function of these motifs in B cells and DCs involved in EAE and TD germinal center responses, we have generated knock-in mice containing distinct CD40 cytoplasmic domain TRAF-binding site mutations and have used these animals, together with bone marrow chimeric mice, to assess the roles that these motifs play in CD40 function. We found that both TRAF2/3 and TRAF6 motifs of CD40 are critically involved in EAE induction and demonstrated that this is mediated by a role of both motifs for priming of pathogenic T cells by DCs. In contrast, the TRAF2/3 binding motif, but not the TRAF6 binding motif, is required for B cell CD40 function in TD high-affinity Ab responses. These data demonstrate that the requirements for expression of specific TRAF-binding CD40 motifs differ for B cells or DCs that function in specific immune responses and thus identify targets for intervention to modulate these responses.

Synergy between anti-commensal antibodies and IL-10 in gut homeostasis and disease

Abstract To limit immune responses to gut-resident microbes, mucus and the epithelial barrier physically separate the host immune system from microbial communities. Immunoglobulin A (IgA) antibodies are known to help to regulate the colonization and functions of mucus-associated commensals. However, the mechanisms whereby other isotypes, including IgG, interface with other components of the immune system to promote tolerance of MA microbes are still being unraveled. Our lab previously showed that, in mice with impaired production of T-dependent (TD) anti-commensal antibodies, IgA- and IgG-mediated recognition of mucus-derived bacterial antigens is significantly reduced. Moreover, transient depletion of IL-10-producing cells from mice devoid of TD antibodies resulted in rapid onset colitis. Therefore, we hypothesized that anti-commensal antibodies synergize with IL-10 to promote immune homeostasis in the colon. Here, we show that, relative to wild type mice, there are increased levels of colonic IL-10-producing CD4 T cells in mice lacking both IgG and IgA (Aicda −/−) but not in mice lacking only IgA (Iga −/−). Additionally, transient depletion of IL-10-producing cells resulted in severe colitis in Aicda −/−but not Iga −/−mice. Importantly, this colitis developed despite elevated levels of IgM in the colon mucus layer of Aicda −/−mice. Furthermore, we observed elevated levels of IgG in the colon mucus layer of Iga −/−mice suggesting a potentially compensatory role for IgG in mice devoid of IgA. Collectively, our data suggest an important contribution for anti-commensal IgG, including in combination with IL-10, in promoting immune tolerance of border-dwelling microbes. R01 AI162736, R21 DK118386

Consequences of maternal breast milk antibodies on neonatal mucosal immunity and intestinal microbe composition

Abstract Breastfeeding is associated with decreased risk of acquiring inflammatory bowel disorders later in life. As breastfeeding is not possible for all mothers and children, having a mechanistic understanding of this process can lead to the development of early-life interventions to foster beneficial host-microbiota relationships, particularly in neonates who are not breastfed. We have shown that mice lacking breast milk antibodies (bmAbs) exhibit dysregulated intestinal homeostasis. These mice harbor increased numbers of live bacteria in the mesenteric lymph nodes and exhibit perturbations in mucosal immunity, including elevated T follicular helper (Tfh) cell and germinal center (GC) B cell responses in the gut-associated lymphoid tissues. Antibodies are key regulators of host-microbiome interactions, and T-dependent (TD) GC derived B cells can persist up to the lifetime of the host. We hypothesize that the TD antibodies generated by the neonate in the absence of bmAbs target resident gut bacteria and lead to long-term alterations in the composition of the microbiota. We performed RT-PCR of the bacterial 16s rRNA gene to quantify the amount of wall-associated microbes in the small and large intestine of mice that received or did not receive bmAbs. To probe the effects of Tfh cells and TD antibodies, we treated half of the mice from each group with anti-ICOS ligand antibody, which blocks Tfh and GC cell formation. We found no significant difference in bacterial burden across all four groups in the small or large intestine. These data suggest that Tfh-cell dependent, bmAb-dependent antibodies do not alter the abundance of wall-associated microbes. Studies are ongoing to determine if bmAbs affect intestinal microbe composition later in life.

Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Renders B Cells Hyperresponsive to Secondary Infections.

Kaposi's sarcoma-associated herpesvirus (KSHV) induces B cell hyperplasia and neoplasia, such as multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL). To explore KSHV-induced B cell reprogramming in vivo, we expressed the KSHV latency locus, inclusive of all viral microRNAs (miRNAs), in B cells of transgenic mice in the absence of the inhibitory FcγRIIB receptor. The BALB/c strain was chosen as this is the preferred model to study B cell differentiation. The mice developed hyperglobulinemia, plasmacytosis, and B lymphoid hyperplasia. This phenotype was ameliorated by everolimus, which is a rapamycin derivative used for the treatment of mantle cell lymphoma. KSHV latency mice exhibited hyperresponsiveness to the T-dependent (TD) antigen mimic anti-CD40 and increased incidence of pristane-induced inflammation. Lastly, the adaptive immunity against a secondary infection with Zika virus (ZIKV) was markedly enhanced. These phenotypes are consistent with KSHV lowering the activation threshold of latently infected B cells, which may be beneficial in areas of endemicity, where KSHV is acquired in childhood and infections are common.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latency in B cells and is stringently linked to primary effusion lymphoma (PEL) and the premalignant B cell hyperplasia multicentric Castleman's disease (MCD). To investigate potential genetic background effects, we expressed the KSHV miRNAs in BALB/c transgenic mice. BALB/c mice are the preferred strain for B cell hybridoma development because of their propensity to develop predictable B cell responses to antigen. The BALB/c latency mice exhibited a higher incidence of B cell hyperplasia as well as sustained hyperglobulinemia. The development of neutralizing antibodies against ZIKV was augmented in BALB/c latency mice. Hyperglobulinemia was dampened by everolimus, a derivative of rapamycin, suggesting a role for mTOR inhibitors in managing immune activation, which is hallmark of KSHV infection as well as HIV infection.

The Effects of Checkpoint Blockade and a CD40 Agonist on Tindependent and T-dependent Antibody Responses in Mice: Implications for Optimization of Vaccination Strategies in Patients Receiving Immunotherapies

Background: Patients with cancer often do not receive vaccines to preventable infectious diseases such as influenza and pneumococcal pneumonia because of a lack of knowledge about the optimal timing of vaccination relative to their underlying disease or their current cancer treatments. Cancer immunotherapies, which rely on the ability to promote immune responsiveness to tumors, are a promising therapeutic modality, but their impact on vaccination is largely unexplored.Methods: We used a pre-clinical mouse model to evaluate the antibody response to a T-dependent (TD) or a Tindependent (TI) antigen immunization with concomitant administration of either checkpoint inhibitors such as antibodies to CTLA-4 or PD-L1 or an antibody to CD40 that has adjuvant properties.Results: We found that checkpoint blockade with anti-CTLA-4 or anti-PD-L1 antibodies provided reduction in IgM, IgG, and most IgG subclasses when immunized with either TI or TD antigens. On the other hand, a CD40 agonist antibody provoked modest reductions in all immunoglobulins in response to TD antigen but provided marked increases in most immunoglobulins and IgG subclasses in response to TI antigen.Conclusions: These data suggest that the timing of vaccinations relative to immunotherapies might be an important factor in determining the efficacy of vaccination. If these findings are shown to extend to humans, the antibody response to vaccination might be attenuated and patients might be at increased risk for infection. This pilot study provides potential mechanistic insights into an important consideration in patients receiving immunotherapies.

IgM+IgD+CD27+ B cells in human: an essential role in the protection against encapsulated bacteria

In humans, CD27+ blood B cells with mutated immunoglobulin (Ig) receptors comprise two major populations: isotype-switched memory cells (IgG+ or IgA+CD27+) and IgM+IgD+CD27+ cells. While switched CD27+ cells are generated in germinal centers (GC) by T-dependent (TD) responses, the origin of IgM+IgD+CD27+ cells is still controversial. Data including ours support the view that these cells can develop and mutate along a GC-independent pathway and that they represent circulating marginal zone B (MZB) cells involved in T-independent (TI) responses. Our data provide evidence for a developmental diversification of these MZB cells, at least in very young children, outside of TD and TI immune responses. The identification of a human MZB cell precursor with NOTCH2-dependent differentiation properties further argue in favor of the existence of a MZB cell lineage in humans, like in rodents. At last, a role for Toll-like receptors in the development and/or maintenance of IgM+IgD+CD27+ B cells is proposed.

B1b cells recognize protective antigens after natural infection and vaccination.

There are multiple, distinct B-cell populations in human beings and other animals such as mice. In the latter species, there is a well-characterized subset of B-cells known as B1 cells, which are enriched in peripheral sites such as the peritoneal cavity but are rare in the blood. B1 cells can be further subdivided into B1a and B1b subsets. There may be additional B1 subsets, though it is unclear if these are distinct populations or stages in the developmental process to become mature B1a and B1b cells. A limitation in understanding B1 subsets is the relative paucity of specific surface markers. In contrast to mice, the existence of B1 cells in human beings is controversial and more studies are needed to investigate the nature of these enigmatic cells. Examples of B1b antigens include pneumococcal polysaccharide and the Vi antigen from Salmonella Typhi, both used routinely as vaccines in human beings and experimental antigens such as haptenated-Ficoll. In addition to inducing classical T-dependent responses some proteins are B1b antigens and can induce T-independent (TI) immunity, examples include factor H binding protein from Borrelia hermsii and porins from Salmonella. Therefore, B1b antigens can be proteinaceous or non-proteinaceous, induce TI responses, memory, and immunity, they exist in a diverse range of pathogenic bacteria, and a single species can contain multiple B1b antigens. An unexpected benefit to studying B1b cells is that they appear to have a propensity to recognize protective antigens in bacteria. This suggests that studying B1b cells may be rewarding for vaccine design as immunoprophylactic and immunotherapeutic interventions become more important due to the decreasing efficacy of small molecule antimicrobials.

Tumor carbohydrate antigens and strategies to develop cancer vaccines and drugs

Certain carbohydrate antigens of malignantly transformed cells have been identified as markers for the onset of cancer and have become targets for the development of anticancer vaccine therapies. For tumor antigens, many carbohydrate antigens belong to T-independent (TI) antigens. Carbohydrate conjugated to protein carriers can switch TI antigen to a T-dependent (TD) antigen. Attempts to add an innate immune response element (such as Toll-like receptor ligand) to carbohydrate TI-antigens have also been studied. Glycosylation inhibitors or small interfering RNA have also been used for antitumor and/or antiviral agents. This review aims at describing the vast spectrum of tumor carbohydrate antigens and strategies to develop cancer vaccines and drugs.

Exposure of a Distinct PDCA-1+ (CD317) B Cell Population to Agonistic Anti-4-1BB (CD137) Inhibits T and B Cell Responses Both In Vitro and In Vivo

4-1BB (CD137) is an important T cell activating molecule. Here we report that it also promotes development of a distinct B cell subpopulation co-expressing PDCA-1. 4-1BB is expressed constitutively, and its expression is increased when PDCA-1+ B cells are activated. We found that despite a high level of surface expression of 4-1BB on PDCA-1+ B cells, treatment of these cells with agonistic anti-4-1BB mAb stimulated the expression of only a few activation markers (B7-2, MHC II, PD-L2), cytokines (IL-12p40/p70), and chemokines (MCP-1, RANTES), as well as sTNFR1, and the immunosuppressive enzyme, IDO. Although the PDCA-1+ B cells stimulated by anti-4-1BB expressed MHC II at high levels and took up antigens efficiently, Ig class switching was inhibited when they were pulsed with T-independent (TI) or T-dependent (TD) Ags and adoptively transferred into syngeneic recipients. Furthermore, when anti-4-1BB-treated PDCA-1+ B cells were pulsed with OVA peptide and combined with Vα2+CD4+ T cells, Ag-specific cell division was inhibited both in vitro and in vivo. Our findings suggest that the 4-1BB signal transforms PDCA-1+ B cells into propagators of negative immune regulation, and establish an important role for 4-1BB in PDCA-1+ B cell development and function.

Multiple routes to B-cell memory

B-cell memory describes the populations of cells that provide long-term humoral immunity: long-lived antibody-secreting plasma cells that reside mainly in the bone marrow and memory B cells. Interestingly, the memory B-cell population is heterogenous, although the importance of this heterogeneity has been unclear. Recent studies have investigated the formation and function of memory in different settings. In particular, T-independent memory-like cells and T-dependent (TD) IgM memory B cells qualitatively differ from canonical TD class-switched memory B cells; however, these studies suggest that IgM memory cells preserve the memory population over long periods of time. These subsets are evocative of the evolution of the humoral immune response, with memory-like cells appearing before acquisition of germinal centers, suggesting that there are multiple pathways to producing B-cell memory.

B cell TLRs and induction of immunoglobulin class-switch DNA recombination

Toll-like receptors (TLRs) are a family of conserved pattern recognition receptors (PRRs). Engagement of B cell TLRs by microbe-associated molecular patterns (MAMPs) induces T-independent (TI) antibody responses and plays an important role in the early stages of T-dependent (TD) antibody responses before specific T cell help becomes available. The role of B cell TLRs in the antibody response is magnified by the synergy of B cell receptor (BCR) crosslinking and TLR engagement in inducing immunoglobulin (Ig) class switch DNA recombination (CSR), which crucially diversifies the antibody biological effector functions. Dual BCR/TLR engagement induces CSR to all Ig isotypes, as directed by cytokines, while TLR engagement alone induces marginal CSR. Integration of BCR and TLR signaling results in activation of the canonical and non-canonical NF-κB pathways, induction of activation-induced cytidine deaminase (AID) and germline transcription of IgH switch (S) regions. A critical role of B cell TLRs in CSR and the antibody response is emphasized by the emergence of several TLR ligands as integral components of vaccines that greatly boost humoral immunity in a B cell-intrinsic fashion.

T cells and follicular dendritic cells in germinal center B‐cell formation and selection

Germinal centers (GCs) are specialized microenvironments formed after infection where activated B cells can mutate their B-cell receptors to undergo affinity maturation. A stringent process of selection allows high affinity, non-self-reactive B cells to become long-lived memory B cells and plasma cells. While the precise mechanism of selection is still poorly understood, the last decade has advanced our understanding of the role of T cells and follicular dendritic cells (FDCs) in GC B-cell formation and selection. T cells and non-T-cell-derived CD40 ligands on FDCs are essential for T-dependent (TD) and T-independent GC formation, respectively. TD-GC formation requires Bcl-6-expressing T cells capable of signaling through SAP, which promotes formation of stable T:B conjugates. By contrast, differentiation of B blasts along the extrafollicular pathway is less dependent on SAP. T-follicular helper (Tfh) cell-derived CD40L, interleukin-21, and interleukin-4 play important roles in GC B-cell proliferation, survival, and affinity maturation. A role for FDC-derived integrin signals has also emerged: GC B cells capable of forming an immune synapse with FDCs have a survival advantage. This emerges as a powerful mechanism to ensure death of B cells that bind self-reactive antigen, which would not normally be presented on FDCs.

CD16/32-specific biotinylated 2.4G2 single-chain Fv complexed with avidin-FITC enhances FITC-specific humoral immune response in vivo in a CD16-dependent manner

Fcgamma receptors (FcgammaRs) play an essential role in the regulation of immune response due to their ability to bind immune complexes. Activating FcgammaRs may facilitate antigen presentation and dendritic-cell maturation, while in the late phase of the immune response, the inhibitory FcgammaRIIb may down-regulate B-cell activation upon cross-linking with activating receptors. In this study, we investigated the in vivo role of FcgammaRs on the modulation of humoral immune response. In order to get well-defined immune complexes that can bind to both the activating and the inhibitory FcgammaRs, we designed a mono-biotinylated single-chain fragment variable construct from the rat anti-mouse CD16/32 clone 2.4G2, linked to avidin-FITC, and tested its effect on the FITC-hapten-specific T-independent type 2 (TI-2) and T-dependent (TD) immune response. When injected intravenously in mice, the complex bound to a small portion of B220+, CD11b(high) and CD11c(high) cells and was localized in the spleen on marginal zone macrophages 15 min after treatment. When applied as a booster following primary immunization with TI-2 (FITC-dextran) or TD (FITC-keyhole limpet haemocyanin) antigens, the complex elevated the number of hapten-specific IgM/IgG-producing B cells. This effect was diminished in CD16KO mice, suggesting that the activating-type FcgammaRIII might be a key mediator of this mechanism.

Antigen-specific responses and ANA production in B6. Sle1b mice: A role for SAP

B6. Sle1b mice, which contain the Sle1b gene interval derived from lupus prone NZM2410 mice on a C57BL/6 background, present with gender-biased, highly penetrant anti-nuclear antibody (ANA) production. To obtain some insight into the possible induction mechanism of autoantibodies in these mice we compared antigen-specific T dependent (TD) and T independent (TI-II) responses between B6. Sle1b and B6 mice before the development of high ANA titers. Our results show that B6. Sle1b mice mount enhanced responses to a TI-II antigen. Additionally, the memory T cell response generated by a TD antigen also increased. This enhancement correlates with the greater ability of B cells from B6. Sle1b mice to present antigen to T cells. The SLAM Associated Protein (SAP) is critical for signaling of many of the molecules encoded by the SLAM/CD2 gene cluster, candidates for mediating the Sle1b phenotype; therefore, we also investigated the effect of sap deletion in these strains on the TD and TI-II responses as well as on ANA production. The results of these studies of responses to non-self-antigens provide further insight into the mechanism by which responses to self-antigens might be initiated in the context of specific genetic alterations.

Conversion of T‐dependent (TD) antigens to T‐independent (TI) antigens: A novel follicular dendritic cell (FDC)‐dependent activity

Conversion of T‐dependent (TD) antigens to T‐independent (TI) antigens: A novel follicular dendritic cell (FDC)‐dependent activity

Sphingosine 1‐phosphate regulates innate and acquired intestinal IgA production

Intestinal IgA plays an important role in the innate and acquired phases of immunosurveillance by recognizing T‐independent (TI) and T‐dependent (TD) antigens, respectively. Sphingosine 1‐phosphate (S1P) is known to regulate lymphocyte emigration from organized lymphoid tissues, but its immunological role in the induction of intestinal IgA production remains to be elucidated. Here we show that intestinal IgA productions against TI and TD antigens are controlled by S1P. We found that disruption of S1P‐mediated signaling by the treatment of mice with FTY720, a modulator of S1P receptors, resulted in the marked reduction of intestinal IgA production against TI phosphorylcholine induced by oral immunization with heat‐killed Streptococcal pneumoniae (R36A). Similarly, FTY720 reduced production of intestinal IgA against ovalbumin (OVA), a typical TD antigen, in mice orally immunized with OVA plus mucosal adjuvant, cholera toxin. The decreased TI and TD antigen‐specific intestinal IgA productions were associated with the impaired trafficking of peritoneal B1 and Peyer s patch B2 cells into the intestinal lamina propria, respectively. These findings point to a pivotal role for S1P in innate and acquired phases of intestinal B cell immunity.

Control of Germinal Center Reaction against T-Independent Antigens by the Fc(alpha)/(mu)Receptor (53.7)

Abstract Germinal center (GC) formation in the secondary lymphoid follicles is induced by immunization with T-independent (TI) as well as T-dependent (TD) antigens. However, structural and functional characteristics of the GC induced by TI antigens have not been elucidated. Here, we show that marginal zone B (MZB) cells and follicular dendritic cells (FDC) preferentially express the Fc receptor for IgM and IgA (Fc(alpha)/(mu)R) as well as the complement receptor CD21/35. Mice deficient in Fc(alpha)/(mu)R showed significantly enhanced GC formation in response to TI antigens, in which both B cells and FDC were involved. Fc(alpha)/(mu)R-deficient mice also showed enhanced TI antigen retention by MZB cells and FDC, CXCL13 expression and affinity maturation of IgG3. Depletion of complements by injection with cobra venom factor completely abrogated this phenotype. These results suggest that Fc(alpha)/(mu)R controls GC reactions and affinity maturation of antibodies against TI antigens by interacting with complement cascades.

Exosome-mediated B cell activation (36.11)

Abstract The mature B cell population is divided into splenic follicular (FO) B, marginal zone (MZ) B and B1 B cells by phenotype, localization, and function. MZ B and B1 B cells participate in the early immune response against blood-borne T-independent (TI) antigens to bridge the temporal gap between the innate and adaptive immune response. We previously described the capture and transport of bacteria to the spleen by blood-derived CD11c immature dendritic cells (DCs), which are responsible for initiating immune responses to TI-2 antigens. However, the molecular basis of the DC-B cell interaction is complex, since supernatant (SN) from bacteria-primed DCs alone initiates antigen (Ag)-specific MZ B cell differentiation in vitro. Therefore, we propose that bacteria-primed DCs release factors able to initiate Ag-specific plasmablast generation. Recent findings that DCs secrete exosomes, which have the ability to stimulate T-dependent (TD) immune responses, support our hypothesis. To determine whether exosomes are involved in TI immune responses, we isolated exosomes from SN of bacteria-primed DCs (BMDC) and cocultured them with splenic B cells from M167 heavy chain transgenic (tg) mice expressing a dominant B cell clone, reactive with phosphorylcholine (PC). Using this system, we show that exosomes isolated from SN of Streptococcus pneumoniae primed BMDCs can specifically activate the M167 B cell clones, but not B cells from hen-egg-lysozyme (HEL)-specific MD4 tg B cell mice. These results suggest an involvement of exosomes in Ag-specific MZ B cell differentiation.

Molecular basis of common variable immunodeficiency

Common variable immunodeficiency (CVID) is the most prevalent human primary immunodeficiency requiring medical attention. Until recently, the only known genetic defect specific to CVID was the inducible costimulatory receptor (ICOS) deficiency, which accounts for less than 1% of the patients. Recently, mutations in the TNF receptor family member transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), which mediates isotype switching in B cells, were found to be present in 10% to 20% of patients with CVID. Mutations in TACI were also found in relatives of patients with CVID who had IgA deficiency (IgAD), as well as in a patient with isolated IgAD. In the majority of patients described to date, only one TACI allele is mutated, showing an autosomal dominant transmission of the disease. B cells from individuals with TACI mutations did not produce IgG and IgA in response to the TACI ligand a proliferation-inducing ligand (APRIL), probably reflecting impaired isotype switching. These results suggest that TACI mutations can lead to CVID and IgAD.