TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen

Tsuji, S.; Stein, Lucas; Kamada, Nobuhiko; Núñez, Gabriel; Bram, Richard J.; Sousa, Ana E.; Platt, Jeffrey L.; Cascalho, Marília

doi:10.1172/jci74428

Cited by 37 publications

(64 citation statements)

References 49 publications

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“…In contrast to earlier publications (3), more recent reports showed diminished sustainment of plasma cells in response to T cell-dependent (TD) antigens in TACI KO mice (6). Interestingly, Tsuji et al reported that despite impaired plasma cell survival and reduced Ab response to TD antigens, TACI KO mice manifest enhanced clearance of the enteric pathogen Citrobacter rodentium, presumably due to generation of higher avidity of Abs in the absence of TACI (7). Whereas TACI is well established as a B-cell receptor, its involvement in innate immune response is less clear.…”

mentioning

confidence: 75%

TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility toLeishmaniainfection

Allman

Dey

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The TNF family member, transmembrane activator and calciummodulator and cyclophilin ligand interactor (TACI), is a key molecule for plasma cell maintenance and is required in infections where protection depends on antibody response. Here, we report that compared with WT mouse, TACI KO Μϕs expressed lower levels of Toll-like receptors (TLRs), CD14, myeloid differentiation primary response protein 88, and adaptor protein Toll/IL-1 receptor domaincontaining adapter-inducing IFN-β and responded poorly to TLR agonists. Analysis of Μϕ phenotype revealed that, in the absence of TACI, Μϕs adapt the alternatively activated (M2) phenotype. Steady-state expression levels for M2 markers IL-4Rα, CD206, CCL22, IL-10, Arg1, IL1RN, and FIZZ1 were significantly higher in TACI KO Μϕ than in WT cells. Confirming their M2 phenotype, TACI-KO Mϕs were unable to control Leishmania major infection in vitro, and intradermal inoculation of Leishmania resulted in a more severe manifestation of disease than in the resistant C57BL/6 strain. Transfer of WT Μϕs to TACI KO mice was sufficient to significantly reduce disease severity. TACI is likely to influence Mϕ phenotype by mediating B cell-activating factor belonging to the TNF family (BAFF) and a proliferation inducing ligand (APRIL) signals because both these ligands down-regulated M2 markers in WT but not in TACI-deficient Μϕs. Moreover, treatment of Μϕs with BAFF or APRIL enhanced the clearance of Leishmania from cells only when TACI is expressed. These findings may have implications for understanding the shortcomings of host response in newborns where TACI expression is reduced and in combined variable immunodeficiency patients where TACI signaling is ablated.T ransmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) is a member of the TNF family molecules (1). It is a receptor for B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL). Although BAFF and APRIL share a second receptor, B-cell maturation antigen (BCMA), BAFF-R only binds to BAFF, and heparan sulfate proteoglycans only engage APRIL. TACI is primarily expressed on mature B cells and mediates signals for Ig isotype switch and secretion (2). Studies in TACI KO mice (3), combined variable immune deficient (CVID) patients with mutations in TACI gene tnfrsf13b (4), and newborns who express severely reduced B-cell TACI (5) all point to its pivotal role in determining antibody (Ab) development against T cell-independent type 2 (TI-2) antigens. In contrast to earlier publications (3), more recent reports showed diminished sustainment of plasma cells in response to T cell-dependent (TD) antigens in TACI KO mice (6). Interestingly, Tsuji et al. reported that despite impaired plasma cell survival and reduced Ab response to TD antigens, TACI KO mice manifest enhanced clearance of the enteric pathogen Citrobacter rodentium, presumably due to generation of higher avidity of Abs in the absence of TACI (7). Whereas TACI is well established as a B-cell receptor, its involvement in innate i...

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mentioning

confidence: 75%

TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility toLeishmaniainfection

Allman

Dey

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, T cell-dependent B cell responses were not affected in mice lacking TACI except for the production of autoreactive IgA [5]. Moreover, in some settings, TACI deficiency resulted in improved T-dependent responses, which were demonstrated in the cases of intestinal pathogens [37], and anti-NP-OVA IgG responses [22], albeit with impaired responses to some T-independent antigens [20,38]. This suggests that inhibition of TACI in humans will maintain T cell-dependent protective B cell functions, providing scope for a significantly improved safety profile over broad B cell-reducing strategies.…”

Section: Discussionmentioning

confidence: 99%

Deleting the BAFF receptor TACI protects against systemic lupus erythematosus without extensive reduction of B cell numbers

Figgett

Deliyanti

Fairfax

et al. 2015

Journal of Autoimmunity

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“…[51, 56] Curiously, humans with TACI deficiency, while sometimes having immunodeficiency, can also mount robust antibody responses. [57] It will be interesting to determine in future studies if clonal expansion of memory B cells is increased in T1D. TACI also influences differentiation of B cells into plasma cells [53, 57–59] and induces IgG and IgA class switch recombination[60–62].…”

Section: Discussionmentioning

confidence: 99%

“…[57] It will be interesting to determine in future studies if clonal expansion of memory B cells is increased in T1D. TACI also influences differentiation of B cells into plasma cells [53, 57–59] and induces IgG and IgA class switch recombination[60–62]. Varying and inconsistent global alterations of IgG or IgA antibodies have been reported in T1D patients.…”

Section: Discussionmentioning

confidence: 99%

Circulating B cells in type 1 diabetics exhibit fewer maturation-associated phenotypes

Hanley

Sutter

Goodman

et al. 2017

Clinical Immunology

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Although autoantibodies have been used for decades as diagnostic and prognostic markers in type 1 diabetes (T1D), further analysis of developmental abnormalities in B cells could reveal tolerance checkpoint defects that could improve individualized therapy. To evaluate B cell developmental progression in T1D, immunophenotyping was used to classify circulating B cells into transitional, mature naïve, mature activated, and resting memory subsets. Then each subset was analyzed for the expression of additional maturation-associated markers. While the frequencies of B cell subsets did not differ significantly between patients and controls, some T1D subjects exhibited reduced proportions of B cells that expressed transmembrane activator and CAML interactor (TACI) and Fas receptor (FasR). Furthermore, some T1D subjects had B cell subsets with lower frequencies of class switching. These results suggest circulating B cells exhibit variable maturation phenotypes in T1D. These phenotypic variations may correlate with differences in B cell selection in individual T1D patients.

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TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen

Cited by 37 publications

References 49 publications

TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility toLeishmaniainfection

TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility toLeishmaniainfection

Deleting the BAFF receptor TACI protects against systemic lupus erythematosus without extensive reduction of B cell numbers

Circulating B cells in type 1 diabetics exhibit fewer maturation-associated phenotypes

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