B cell clones that sustain long-term plasmablast growth in T-independent extrafollicular antibody responses

Hsu, Mei‐Chi; Toellner, Kai‐Michael; Vinuesa, Carola G.; MacLennan, Ian C. M.

doi:10.1073/pnas.0601502103

Cited by 132 publications

(179 citation statements)

References 40 publications

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“…Preponderant evidence supports MZB cells as the major responder to the TI antigen NP-Ficoll (35,36). The lack of both of MZB and B-1 cells may explain the impaired TI antibody responses in bumble mice, but because transfer of wt peritoneal cells to bumble partially restored antibody responses to NP-Ficoll, our data illustrate that B-1 cells mediate at least some of the response to this antigen, as has previously been demonstrated (37).…”

Section: Cd93supporting

confidence: 62%

B-1a transitional cells are phenotypically distinct and are lacking in mice deficient in IκBNS

Pedersen

Ádori

Khoenkhoen

et al. 2014

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

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Significance A subpopulation of antibody-secreting cells, B-1 cells, provides early protection against several types of pathogens. Both the development and function differ between B-1 cells and the better known B-2 cells, and exclusively B-1 cells are lacking in mice deficient for the nuclear inhibitory κB protein, IκBNS. B-1 cells mature similar to B-2 cells via a transitional stage. We demonstrate here the existence of a phenotypically distinct B-1 transitional B (TrB)-cell population in the neonatal spleen of wild-type mice. This TrB-1a–cell subset was lost in the absence of IκBNS, thus revealing a requirement for intact NF-κB signaling via IκBNS during this stage of the development of B-1 cells. Learning more about the development of B-1 cells may reveal new targets for therapeutic intervention.

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Section: Cd93supporting

confidence: 62%

B-1a transitional cells are phenotypically distinct and are lacking in mice deficient in IκBNS

Pedersen

Ádori

Khoenkhoen

et al. 2014

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

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“…These observations confirm previous studies showing that CTA1-DD acted independently of TLR signaling and also had no polyclonal B cell-activating effect in vivo (13,19). In the current study, we consistently failed to demonstrate an effect of CTA1-DD on GC reactions or Ab responses to NP-Ficoll or NP-dextran, responses known to depend on extrafollicular Ab production primarily by B1b cells and possibly MZ B cells (63). It should be noted, though, that this result is at variance with an earlier report, in which we showed that both GC reactions and serum Abs were upregulated to DNP-dextran by CTA1-DD (17).…”

Section: Discussionsupporting

confidence: 77%

Complement Activation and Complement Receptors on Follicular Dendritic Cells Are Critical for the Function of a Targeted Adjuvant

Mattsson

Stensson

Schön

et al. 2011

The Journal of Immunology

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A detailed understanding of how activation of innate immunity can be exploited to generate more effective vaccines is critically required. However, little is known about how to target adjuvants to generate safer and better vaccines. In this study, we describe an adjuvant that, through complement activation and binding to follicular dendritic cells (FDC), dramatically enhances germinal center (GC) formation, which results in greatly augmented Ab responses. The nontoxic CTA1-DD adjuvant hosts the ADP-ribosylating CTA1 subunit from cholera toxin and a dimer of the D fragment from Staphylococcus aureus protein A. We found that T cell-dependent, but not -independent, responses were augmented by CTA1-DD. GC reactions and serum Ab titers were both enhanced in a dose-dependent manner. This effect required complement activation, a property of the DD moiety. Deposition of CTA1-DD to the FDC network appeared to occur via the conduit system and was dependent on complement receptors on the FDC. Hence, Cr2−/− mice failed to augment GC reactions and exhibited dramatically reduced Ab responses, whereas Ribi adjuvant demonstrated unperturbed adjuvant function in these mice. Noteworthy, the adjuvant effect on priming of specific CD4 T cells was found to be intact in Cr2−/− mice, demonstrating that the CTA1-DD host both complement-dependent and -independent adjuvant properties. This is the first demonstration, to our knowledge, of an adjuvant that directly activates complement, enabling binding of the adjuvant to the FDC, which subsequently strongly promoted the GC reaction, leading to augmented serum Ab titers and long-term memory development.

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“…We used the mouse neuroblastoma cell line, Neuro‐2a (N2a), stably expressing under the control of a tetracycline‐regulated promoter full‐length (441 residues) human tau (hTau40, which indicates tau protein with 2N and 4R domains (2N4R‐tau)) as wild‐type (WT) or with mutations A152T or P301L (Khlistunova et al ., 2006). The CMA receptor LAMP‐2A was knocked down using siRNA (Massey et al ., 2006). In agreement with our previous observations (Wang et al ., 2009), we found that lysosomes contribute to degradation of WT tau (reflected as an increase in tau levels upon blockage of lysosomal proteolysis with inhibitors).…”

Section: Resultsmentioning

confidence: 99%

“…The mouse neuroblastoma cell line Neuro‐2a (N2a) was generated as described before (Khlistunova et al ., 2006). Cells stably knocked down for LAMP‐2A, Atg7 were generated as described previously (Massey et al ., 2006) using lentiviral‐delivered small hairpin RNA (shRNA). Cells stably knocked down for Vps4A/B were generated by similar procedures but using the following shRNA from the Mission‐Sigma library (Sigma‐Aldrich, San Luis, MO, USA) VPS4A (TRCN0000101417) and VPS4B (TRCN0000101821).…”

Section: Methodsmentioning

confidence: 99%

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Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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SummaryLoss of neuronal proteostasis, a common feature of the aging brain, is accelerated in neurodegenerative disorders, including different types of tauopathies. Aberrant turnover of tau, a microtubule‐stabilizing protein, contributes to its accumulation and subsequent toxicity in tauopathy patients’ brains. A direct toxic effect of pathogenic forms of tau on the proteolytic systems that normally contribute to their turnover has been proposed. In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone‐mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age‐related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk‐associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in tau or known to promote its aggregation. Interestingly, although most mutations markedly reduced degradation of tau through autophagy, the step of this process preferentially affected varies depending on the type of tau mutation. Overall, our studies unveil a complex interplay between the multiple modifications of tau and selective forms of autophagy that may determine its physiological degradation and its faulty clearance in the disease context.

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B cell clones that sustain long-term plasmablast growth in T-independent extrafollicular antibody responses

Cited by 132 publications

References 40 publications

B-1a transitional cells are phenotypically distinct and are lacking in mice deficient in IκBNS

B-1a transitional cells are phenotypically distinct and are lacking in mice deficient in IκBNS

Complement Activation and Complement Receptors on Follicular Dendritic Cells Are Critical for the Function of a Targeted Adjuvant

Interplay of pathogenic forms of human tau with different autophagic pathways

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