Clifford Snapper - Academia.edu (original) (raw)

Papers by Clifford Snapper

Journal of Experimental Medicine, 1992

T cell-independent type 2 (TI-2), in contrast to T-dependent, antigens stimulate the production o... more T cell-independent type 2 (TI-2), in contrast to T-dependent, antigens stimulate the production of murine IgG3. To investigate a possible role for cytokines in mediating the induction of this IgG subclass, we established an in vitro polyclonal model system for studying TI-2 antigen-mediated B cell activation by using dextran-conjugated anti-IgD antibody (o~6-dex). We demonstrate that interferon "r (IFN-7) stimulates, and interleukin 4 inhibits, the expression of IgG3 by c~&dexactivated cells. The production of IFN-'r by non-T cells in response to bacterial products, possibly capsular polysaccharides, may provide an explanation underlying the ability of TI antigens, which are unable to directly stimulate T cell-derived cytokines to induce Ig isotype switching.

Journal of Experimental Medicine, 1988

Current Protein & Peptide Science, 2006

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Summary Bacterial lipopolysaccharide (LPS) has been reported to induce immunoglobulin (Ig)G2b cla... more Summary Bacterial lipopolysaccharide (LPS) has been reported to induce immunoglobulin (Ig)G2b class switching, yet we observed strain differences in IgG2b secretion in response to this mitogen. Specifically, BALB/c B cells, unlike those from DBA/2, synthesized relatively low amounts of IgG2b relative to IgG3, IgG1, or IgM. This report demonstrates that transforming growth factor (TGF)31, previously shown to induce IgA dass

Infection and immunity, 1998

Antibody to pneumococcal surface protein A (PspA) has been shown to be protective for Streptococc... more Antibody to pneumococcal surface protein A (PspA) has been shown to be protective for Streptococcus pneumoniae infections in mice. In an attempt to define a model for inducing protective antibody to PspA in the absence of adjuvant, we designed two genetic fusions, PspA-interleukin-2 [IL-2]) and PspA-granulocyte-macrophage colony-stimulating factor (GM-CSF). These constructs maintained high cytokine function in vitro, as tested by their activity on IL-2 or GM-CSF-dependent cell lines. While intranasal immunization with PspA induced no detectable anti-PspA response, both PspA-IL-2 and PspA-GM-CSF stimulated high immunoglobulin G1 (IgG1) antibody responses. Interestingly, only the PspA-IL-2, not the PspA-GM-CSF, construct stimulated IgG2a antibody responses, suggesting that this construct directed the response along a TH1-dependent pathway. Comparable enhancement of the anti-PspA response with similar isotype profiles was observed after subcutaneous immunization as well. The enhancemen...

Infection and immunity, 1997

Resting B cells stimulated with dextran-conjugated anti-immunoglobulin D (anti-IgD) antibodies (a... more Resting B cells stimulated with dextran-conjugated anti-immunoglobulin D (anti-IgD) antibodies (anti-Ig-dex), a model for B-cell activation in response to polysaccharide antigens, proliferate but secrete little if any Ig, unless additional stimuli are present. In order to elucidate the parameters which costimulate T-cell-independent antipolysaccharide antibody responses during bacterial infections, we tested the capacities of highly purified porin proteins from Neisseria meningitidis and Neisseria gonorrhoeae to augment in vitro proliferation and induce Ig secretion by anti-Ig-dex-activated B cells. Resting B cells, from lipopolysaccharide (LPS)-nonresponsive C3H/HeJ mice, proliferated and secreted IgM in response to each of three distinct porins acting alone. Further, porins, even at concentrations that were minimally inductive when acting alone, were strongly synergistic with anti-Ig-dex for proliferation and Ig secretion. Similar synergistic effects of porins with CD40-ligand wer...

Journal of immunology (Baltimore, Md. : 1950), 1995

The parameters necessary for induction of high-rate IgA class switching are unknown. Thus, althou... more The parameters necessary for induction of high-rate IgA class switching are unknown. Thus, although TGF-beta is switch factor for the IgA class, the percentage of membrane (m)IgA+ cells generated in vitro in response to TGF-beta and various individual modes of B cell activation is limited to 1 to 2% of the total B cell population, a percentage far below that observed within Peyer's patches. In this report we determined a set of parameters that act synergistically to generate up to 15 to 20% mIgA+ cells in vitro. A dual mode of B cell activation is required whereby signaling through CD40 or in response to LPS stimulation must occur in concert with multivalent Ag receptor crosslinking. A complex cytokine requirement is also revealed in that both IL-4 and IL-5 must be present with TGF-beta for high-rate IgA class switching to occur. By contrast, IFN-gamma, a known antagonist of IL-4, strongly suppresses the induction of mIgA+ cells in response to these stimuli. This novel cellular ...

Trends in Immunology, 2001

Studies have indicated that purified soluble polysaccharide antigens can elicit T cell-independen... more Studies have indicated that purified soluble polysaccharide antigens can elicit T cell-independent Ig responses in vivo, although these responses can be modulated by T cells in a noncognate manner. Relatively little is known, however, concerning the parameters that regulate polysaccharide-specific, as well as protein-specific, Ig isotype responses to an intact extracellular bacterium. Using the murine in vivo humoral response to intact Streptococcus pneumoniae as a model it can be shown that CD4+ T-cell receptor alphabeta+ T cells deliver help for both polysaccharide- and protein-specific Ig responses. However, these responses differ fundamentally in their mechanism of action.

Immunology Today, 1993

leading to Ig isotype switching in response to 7"I antigens.

ncbi.nlm.nih.gov

Antigens and infectious agents that stimulate interferon ot(IFN-t~) production in mice induce ant... more Antigens and infectious agents that stimulate interferon ot(IFN-t~) production in mice induce antibody responses that are predominantly of the immunoglobulin (Ig)G2a isotype and contain little or no IgE. This suggested the possibility that IFN-ot might have a role in directing Ig isotype selection. Consistent with this possibility, we have found that injection of mice with recombinant mouse IFN-ol suppresses IgE secretion, enhances IgG2a secretion, and has no independent effect on IgG1 secretion in mice stimulated with a foreign anti-IgD antibody. Injection of mice with polyinosinic acid.polycytidylic acid (poly I.C), an inducer of macrophage IFN-ol production, also suppresses the anti-IgD antibody-induced IgE response and stimulates the IgG2a response; these effects are blocked by a sheep antibody that neutralizes mouse IFN-oL//~ Both recombinant IFN-c~ and poly I-C have maximum IgE suppressive and IgG2a stimulatory effects when injected early in the anti-IgD antibody-induced immune response. Addition of IFN-ot to mouse B cells cultured with lipopolysaccharide (LPS) + interleukin 4(I1,4) suppresses both IgG1 and IgE production, but much less potently than IFN-% IFN-c~ suppresses anti-IgD antibodyinduced increases in the level of splenic I1,4 mRNA, but enhances the anti-IgD antibody-induced increase in the splenic level of IFN-3' mRNA. These results are consistent with the effect of IFN-o~ on Ig isotype expression in mice, as I1,4 stimulates IgE and suppresses IgG2a secretion while IFN-3" exerts opposite effects. These observations suggest that antigen presenting cells, by secreting IFN-oe early in the course of an immune response, can influence the nature of that response both through direct effects on B cells and by influencing the differentiation of T cells.

The Journal of Immunology, 2005

The Journal of Immunology, 2000

The Journal of Immunology, 2007

The Journal of Immunology, 2008

Streptococcus pneumoniae (Pn) are both dependent on CD4 ؉ T cell help, B7-dependent costimulation... more Streptococcus pneumoniae (Pn) are both dependent on CD4 ؉ T cell help, B7-dependent costimulation, and CD40/CD40 ligand interactions. However, the primary PS-specific, relative to protein-specific, IgG response terminates more rapidly, requires a shorter period of T cell help and B7-dependent costimulation, and fails to generate memory. In light of the critical role for ICOS/ICOS ligand interactions in sustaining T cell-dependent Ig responses and promoting germinal center reactions, we hypothesized that this interaction was nonessential for PS-specific IgG responses to Pn. We now demonstrate that ICOS ؊/؊ , relative to wild-type, mice elicit a normal PS-specific IgG isotype response to Pn, despite marked inhibition of both the primary and secondary IgG anti-protein (i.e., PspA, PspC, and PsaA) response. A blocking anti-ICOS ligand mAb injected during primary Pn immunization inhibits both the primary anti-protein response and the generation of protein-specific memory, but has no effect when injected during secondary immunization. In contrast to Pn, both PSand protein-specific IgG responses to a pneumococcal conjugate vaccine are inhibited in ICOS ؊/؊ mice. ICOS ؊/؊ mice immunized with intact Pn or conjugate exhibit nearly complete abrogation in germinal center formation. Finally, although mice that lack the adaptor molecule SAP (SLAM-associated protein) resemble ICOS ؊/؊ mice (and can exhibit decreased ICOS expression), we observe that the PS-specific, as well as protein-specific, IgG responses to both Pn and conjugate are markedly defective in SAP ؊/؊ mice. These data define a novel T cell-, SAP-, and B7-dependent, but ICOS-independent, extrafollicular pathway of Ig induction.

The Journal of Immunology, 2006

Exosomes derived from dendritic cells (DC) activate T cells in vivo, but whether exosomes are abl... more Exosomes derived from dendritic cells (DC) activate T cells in vivo, but whether exosomes are able to induce and/or modulate humoral immune responses is still unknown. We show that murine bone marrow DC pulsed in vitro with an intact protein (diphtheria toxoid (DT)) produce exosomes that induce, in the absence of free protein, in vivo Ig responses specific for DT in naive recipients. Furthermore, these exosomes stimulate secondary IgG anti-DT responses in mice primed with intact DT. Exosomes from mature, relative to immature, DC were more effective at inducing primary, although not secondary, IgG anti-DT responses. Whereas intact DT preferentially induced a type 2 (IgG1) anti-DT response, exosomes from DT-pulsed bone marrow DC favored induction of type 1 (IgG2b and IgG2a) DT-specific IgG. These results are the first to demonstrate the ability of exosomes derived from Ag-pulsed DC to induce and modulate Ag-specific humoral immunity in vivo.

The Journal of Immunology, 2009

During infections with extracellular bacteria, such as Streptococcus pneumoniae (Pn), the immune ... more During infections with extracellular bacteria, such as Streptococcus pneumoniae (Pn), the immune system likely encounters bacterial components in soluble form, as well as those associated with the intact bacterium. The potential cross-regulatory effects on humoral immunity in response to these two forms of Ag are unknown. We thus investigated the immunologic consequences of coimmunization with intact Pn and soluble conjugates of Pn-derived proteins and polysaccharides (PS) as a model. Coimmunization of mice with Pn and conjugate resulted in marked inhibition of conjugate-induced PS-specific memory, as well as primary and memory anti-protein Ig responses. Inhibition occurred with unencapsulated Pn, encapsulated Pn expressing different capsular types of PS than that present in the conjugate, and with conjugate containing protein not expressed by Pn, but not with 1-m latex beads in adjuvant. Inhibition was long-lasting and occurred only during the early phase of the immune response, but it was not associated with tolerance. Pn inhibited the trafficking of conjugate from the splenic marginal zone to the B cell follicle and T cell area, strongly suggesting a potential mechanism for inhibition. These data suggest that during infection, bacterial-associated Ags are the preferential immunogen for antibacterial Ig responses.

The Journal of Immunology, 2013

Intact Streptococcus pneumoniae expressing type 14 capsular polysaccharide (PPS14) and type III S... more Intact Streptococcus pneumoniae expressing type 14 capsular polysaccharide (PPS14) and type III S. agalactiae containing a PPS14 core capsule identical to PPS14 exhibit noncovalent associations of PPS14 and bacterial protein, in contrast to soluble covalent conjugates of these respective Ags. Both bacteria and conjugates induce murine PPS14-specific IgG responses dependent on CD4⁺ T cells. Further, secondary immunization with conjugate and S. agalactiae, although not S. pneumoniae, results in a boosted response. However, in contrast to conjugate, PPS14-specific IgG responses to bacteria lack affinity maturation use the 44.1-idiotype and are dependent on marginal zone B cells. To better understand the mechanism underlying this dichotomy, we developed a minimal model of intact bacteria in which PPS14 and pneumococcal surface protein A (PspA) were stably attached to 1 μm (bacteria-sized) latex beads, but not directly linked to each other, in contrast to PPS14-PspA conjugate. Beads coated simultaneously with PPS14+[PspA], similar to conjugate, induced in mice boosted PPS14-specific IgG secondary responses, dependent on T cells and ICOS-dependent costimulation, and in which priming could be achieved with PspA alone. In contrast to conjugate, but similar to intact bacteria, the primary PPS14-specific IgG response to beads coated simultaneously with PPS14+[PspA] peaked rapidly, with the secondary response highly enriched for the 44.1-idiotype and lacking affinity maturation. These results demonstrate that noncovalent association in a particle, of polysaccharide and protein, recapitulates essential immunologic characteristics of intact bacteria that are distinct from soluble covalent conjugates of these respective Ags.

The Journal of Immunology, 2012

We previously reported distinct differences in the murine in vivo Ig polysaccharide (PS)-specific... more We previously reported distinct differences in the murine in vivo Ig polysaccharide (PS)-specific responses to intact Streptococcus pneumoniae compared with responses to Neisseria meningitidis and that in each case, the bacterial subcapsular domain markedly influences the Ig response to the associated PS. In light of potentially unique contributions of biochemically distinct capsular PS and/or their characteristic attachments to the underlying bacterium, it remains unresolved whether different bacterial subcapsular domains can exert differential effects on PS-specific Ig responses to distinct bacterial pathogens. In this report, we used a mutant strain of group B Streptococcus (Streptococcus agalactiae) type III (GBS-III) that expresses desialylated capsular polysaccharide of GBS-III, biochemically identical to capsular pneumococcal polysaccharide type 14 (PPS14) of Streptococcus pneumoniae (intact inactivated Streptococcus pneumoniae, capsular type 14, Pn14), directly to compare the in vivo PPS14-specific IgG responses to two distinct Gram-positive bacteria. Although both GBS-III and Pn14 elicited relatively rapid primary PPS14specific IgG responses dependent on CD4 + T cells, B7-dependent costimulation, and CD40-CD40L interactions, only GBS-III induced a highly boosted ICOS-dependent PPS14-specific IgG response after secondary immunization. Of note, priming with Pn14 and boosting with GBS-III, although not isolated PPS14, elicited a similar boosted PPS14-specific IgG response that was dependent on CD4 + T cells during secondary immunization, indicating that Pn14 primes for memory but, unlike GBS-III, fails to elicit it. The inability of Pn14 to elicit a boosted PPS14-specific IgG response was overcome by coimmunization with unencapsulated GBS-III. Collectively, these data establish that structurally identical capsular PS expressed by two distinct Gram-positive extracellular bacteria can indeed elicit distinct PS-specific IgG responses in vivo.