scholarly journals 4-1BB (CD137) Differentially Regulates Murine In Vivo Protein- and Polysaccharide-Specific Immunoglobulin Isotype Responses to Streptococcus pneumoniae

2003 ◽  
Vol 71 (1) ◽  
pp. 196-204 ◽  
Author(s):  
Zheng-Qi Wu ◽  
Abdul Q. Khan ◽  
Yi Shen ◽  
Karen M. Wolcott ◽  
Wojciech Dawicki ◽  
...  
Keyword(s):  
T Cells ◽  
Streptococcus Pneumoniae ◽  
Protein A ◽  
Teichoic Acid ◽  
Surface Protein ◽  
Cell Receptor ◽  
Primary Response ◽  
Humoral Immune ◽  
Specific Immunoglobulin

ABSTRACT 4-1BB (CD137) is induced on activated CD4+ and CD8+ T cells and delivers a costimulatory signal upon binding the 4-1BB ligand (4-1BBL) expressed on antigen-presenting cells. Induction of 4-1BB is dependent on activation via the T-cell receptor (TCR) and possibly CD28. It was previously demonstrated that both an in vivo protein (pneumococcal surface protein A [PspA])- and polysaccharide (phosphorylcholine [PC] determinant of teichoic acid)-specific immunoglobulin (Ig) isotype response to Streptococcus pneumoniae was dependent on CD4+ TCRαβ+ T cells and B7-dependent costimulation through CD28. We thus postulated that 4-1BB costimulation would also play a role in regulating the in vivo anti-PspA and anti-PC response to S. pneumoniae. We demonstrate that mice genetically deficient in 4-1BBL elicit a markedly reduced IgM and IgG anti-PC but normal primary and secondary IgG anti-PspA responses to S. pneumoniae relative to those for wild-type mice. However, injection of an agonistic anti-4-1BB monoclonal antibody (MAb), while having no significant effect on the anti-PC response, strongly inhibits the primary anti-PspA response, the generation of PspA-specific memory, and germinal center formation but does not induce a lasting state of tolerance. In contrast, anti-4-1BB MAb has no effect on the anti-PspA response when injected only at the time of secondary immunization. Delay of the addition of anti-4-1BB leads to progressively less inhibition of the primary response up to day 8. This inhibition is independent of CD8+ T cells and is associated with the expansion of CD4+ T cells with an activated phenotype, which is partly dependent on B7-dependent costimulation. These data are the first to suggest a stimulatory role for endogenous 4-1BB-4-1BBL interactions during a humoral immune response to a pathogen and further underscore significant differences in costimulation requirements for an in vivo protein- versus polysaccharide-specific Ig isotype response to an extracellular bacterium.

scholarly journals Both Innate Immunity and Type 1 Humoral Immunity to Streptococcus pneumoniae Are Mediated by MyD88 but Differ in Their Relative Levels of Dependence on Toll-Like Receptor 2

2005 ◽  
Vol 73 (1) ◽  
pp. 298-307 ◽  
Author(s):  
Abdul Q. Khan ◽  
Quanyi Chen ◽  
Zheng-Qi Wu ◽  
James C. Paton ◽  
Clifford M. Snapper
Keyword(s):  
Streptococcus Pneumoniae ◽  
Humoral Immunity ◽  
Protein A ◽  
Surface Protein ◽  
Lethal Challenge ◽  
Humoral Immune ◽  
Extracellular Bacterium

ABSTRACT Little is known regarding the role of Toll-like receptors (TLRs) in regulating protein- and polysaccharide-specific immunoglobulin (Ig) isotype production in response to an in vivo challenge with an extracellular bacterium. In this report we demonstrate that MyD88−/−, but not TLR2−/−, mice are markedly defective in their induction of multiple splenic proinflammatory cytokine- and chemokine-specific mRNAs after intraperitoneal (i.p.) challenge with heat-killed Streptococcus pneumoniae capsular type 14 (S. pneumoniae type 14). This is correlated with analogous responses in splenic cytokine protein release in vitro following addition of S. pneumoniae type 14. Consistent with these data, naïve MyD88−/−, but not TLR2−/−, mice are more sensitive to killing following i.p. challenge with live S. pneumoniae type 14, relative to responses in wild-type mice. However, prior immunization of MyD88−/− mice with heat-killed S. pneumoniae type 14 protects against an otherwise-lethal challenge with live S. pneumoniae type 14. Surprisingly, both MyD88−/− and TLR2−/− mice exhibit striking and equivalent defects in elicitation of type 1 IgG isotypes (IgG3, IgG2b, and IgG2a), but not the type 2 IgG isotype, IgG1, specific for several protein and polysaccharide antigens, in response to i.p. challenge with heat-killed S. pneumoniae type 14. Of note, the type 1 IgG isotype titers specific for pneumococcal surface protein A are reduced in MyD88−/− mice but not TLR2−/− mice. These data suggest that distinct TLRs may differentially regulate innate versus adaptive humoral immunity to intact S. pneumoniae and are the first to implicate a role for TLR2 in shaping an in vivo type 1 IgG humoral immune response to a gram-positive extracellular bacterium.

scholarly journals Major histocompatibility complex-specific prolongation of murine skin and cardiac allograft survival after in vivo depletion of V beta+ T cells.

1993 ◽  
Vol 177 (1) ◽  
pp. 35-44 ◽  
Author(s):  
J A Goss ◽  
R Pyo ◽  
M W Flye ◽  
J M Connolly ◽  
T H Hansen
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Intraperitoneal Administration ◽  
Cell Receptor ◽  
Primary Response ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Allogeneic Response

The preferential usage of certain T cell receptor (TCR) V beta genes has been well established in several major histocompatibility complex (MHC)-restricted immune responses. However, V beta usage among allogeneic responses remains unclear. Because recent findings of ours and others indicate that V beta 8 predominates in certain Ld-restricted, peptide-specific responses, we examined the V beta 8 usage in allogeneic responses to Ld. To selectively recognize the Ld molecule, cells from BALB/c-H-2dm2 (dm2), the Ld-loss mutant mouse, were stimulated in vitro or in vivo with wild-type BALB/c cells. We report here that after the intraperitoneal administration of the anti-V beta 8 monoclonal antibody (mAb) F23.1, peripheral V beta 8 T cells were depleted from dm2 mice. This in vivo depletion abrogated the ability of dm2 splenocytes to mount a primary response to Ld molecules. This abrogation was specific, since the response of V beta 8-depleted dm2 cells to Kb/Db antigens was the same as that of control nondepleted dm2 cells. Furthermore, in vivo depletion of V beta 8 cells was found to cause a dramatic prolongation of Ld-disparate skin grafts (mean survival time [MST] 22.1 +/- 2.1 vs. 10.3 +/- 1.1 d for saline-treated controls, or 10.9 +/- 1.7 d for controls treated with mAb KJ23 to V beta 17). By contrast, V beta 8 depletion had no effect on recipients grafted with haplotype-mismatched skin or single Dk-locus-disparate skin. These findings demonstrate that V beta 8+ T cells predominate in allogeneic response to Ld but not other alloantigens. The effect of V beta 8 depletion was found to be even more dramatic on recipients grafted with Ld-disparate vascularized heart transplants (MST > 100 vs. 8.6 +/- 0.5 d for controls). In total, these findings establish the efficacy of using mAb to the V beta gene family to specifically and significantly enhance the survival of allografts. The implications of detecting V beta 8 usage in both alloreactive or MHC-restricted TCR responses to the same class I molecule are discussed.

scholarly journals Protection against Nasopharyngeal Colonization by Streptococcus pneumoniae Is Mediated by Antigen-Specific CD4+ T Cells

2008 ◽  
Vol 76 (6) ◽  
pp. 2678-2684 ◽  
Author(s):  
Krzysztof Trzciński ◽  
Claudette M. Thompson ◽  
Amit Srivastava ◽  
Alan Basset ◽  
Richard Malley ◽  
...  
Keyword(s):  
T Cells ◽  
Streptococcus Pneumoniae ◽  
T Cell ◽  
Protein A ◽  
Specific Antigen ◽  
Surface Protein ◽  
Bacterial Clearance ◽  
Antigen Specificity ◽  
Nasopharyngeal Colonization ◽  
Pneumococcal Colonization

ABSTRACT CD4+ T-cell-dependent acquired immunity confers antibody-independent protection against pneumococcal colonization. Since this mechanism is poorly understood for extracellular bacteria, we assessed the antigen specificity of the induction and recall of this immune response by using BALB/c DO11.10Rag−/− mice, which lack mature B and T cells except for CD4+ T cells specific for the OVA323-339 peptide derived from ovalbumin. Serotype 6B Streptococcus pneumoniae strain 603S and unencapsulated strain Rx1ΔlytA were modified to express OVA323-339 as a fusion protein with surface protein A (PspA) (strains 603OVA1 and Rx1ΔlytAOVA1) or with PspA, neuraminidase A, and pneumolysin (Rx1ΔlytAOVA3). Whole-cell vaccines (WCV) were made of ethanol-killed cells of Rx1ΔlytA plus cholera toxin (CT) adjuvant, of Rx1ΔlytAOVA1 + CT (WCV-OVA1), and of Rx1ΔlytAOVA3 + CT (WCV-OVA3). Mice intranasally immunized with WCV-OVA1, but not with WCV or CT alone, were protected against intranasal challenge with 603OVA1. There was no protection against strain 603S in mice immunized with WCV-OVA1. These results indicate antigen specificity of both immune induction and the recall response. Effector action was not restricted to antigen-bearing bacteria since colonization by 603S was reduced in animals immunized with vaccines made of OVA-expressing strains when ovalbumin or killed Rx1ΔlytAOVA3 antigen was administered around the time of challenge. CD4+ T-cell-mediated protection against pneumococcal colonization can be induced in an antigen-specific fashion and requires specific antigen for effective bacterial clearance, but this activity may extend beyond antigen-expressing bacteria. These results are consistent with the recruitment and/or activation of phagocytic or other nonspecific effectors by antigen-specific CD4+ T cells.

scholarly journals Generation and Properties of a Streptococcus pneumoniae Mutant Which Does Not Require Choline or Analogs for Growth

1998 ◽  
Vol 180 (8) ◽  
pp. 2093-2101 ◽  
Author(s):  
Janet Yother ◽  
Klaus Leopold ◽  
Johanna White ◽  
Werner Fischer
Keyword(s):  
Streptococcus Pneumoniae ◽  
Stationary Phase ◽  
Cell Walls ◽  
Parent Strain ◽  
Protein A ◽  
Teichoic Acid ◽  
Surface Protein ◽  
Chain Structure ◽  
Wall Teichoic Acid ◽  
Mutant Cells

A mutant (JY2190) of Streptococcus pneumoniae Rx1 which had acquired the ability to grow in the absence of choline and analogs was isolated. Lipoteichoic acid (LTA) and wall teichoic acid (TA) isolated from the mutant were free of phosphocholine and other phosphorylated amino alcohols. Both polymers showed an unaltered chain structure and, in the case of LTA, an unchanged glycolipid anchor. The cell wall composition was also not altered except that, due to the lack of phosphocholine, the phosphate content of cell walls was half that of the parent strain. Isolated cell walls of the mutant were resistant to hydrolysis by pneumococcal autolysin (N-acetylmuramyl-l-alanine amidase) but were cleaved by the muramidases CPL and cellosyl. The lack of active autolysin in the mutant cells became apparent by impaired cell separation at the end of cell division and by resistance against stationary-phase and penicillin-induced lysis. As a result of the absence of choline in the LTA, pneumococcal surface protein A (PspA) was no longer retained on the cytoplasmic membrane. During growth in the presence of choline, which was incorporated as phosphocholine into LTA and TA, the mutant cells separated normally, did not release PspA, and became penicillin sensitive. However, even under these conditions, they did not lyse in the stationary phase, and they showed poor reactivity with antibody to phosphocholine and an increased release of C-polysaccharide from the cell. In contrast to ethanolamine-grown parent cells (A. Tomasz, Proc. Natl. Acad. Sci. USA 59:86–93, 1968), the choline-free mutant cells retained the capability to undergo genetic transformation but, compared to Rx1, with lower frequency and at an earlier stage of growth. The properties of the mutant could be transferred to the parent strain by DNA of the mutant.

scholarly journals Pneumococcal Surface Protein A Inhibits Complement Activation by Streptococcus pneumoniae

1999 ◽  
Vol 67 (9) ◽  
pp. 4720-4724 ◽  
Author(s):  
Anh-Hue T. Tu ◽  
Robert L. Fulgham ◽  
Mark A. McCrory ◽  
David E. Briles ◽  
Alexander J. Szalai
Keyword(s):  
Streptococcus Pneumoniae ◽  
Defense Mechanisms ◽  
Alternative Pathway ◽  
Protein A ◽  
Surface Protein ◽  
Serum Complement ◽  
Factor B ◽  
Pneumococcal Surface Protein A

ABSTRACT Pneumococcal surface protein A (PspA) is a surface-exposed protein virulence factor for Streptococcus pneumoniae. In this study, no significant depletion of serum complement was observed for the serum of mice infected with pneumococci that express PspA. In contrast, in mice infected with an isogenic strain of pneumococci lacking PspA, significant activation of serum complement was detected within 30 min after infection. Also, the PspA-deficient strain but not the PspA-expressing strain was cleared from the blood within 6 h. The contribution of PspA to pneumococcal virulence was further investigated by using mice deficient for C5, C3, or factor B. In mice deficient for C3 or factor B, PspA-negative pneumococci became fully virulent. In contrast, in C5-deficient mice as in wild-type mice, PspA-deficient pneumococci were avirulent. These in vivo data suggest that, in nonimmune mice infected with pneumococci, PspA interferes with complement-dependent host defense mechanisms mediated by factor B. Immunoblots of pneumococci opsonized in vitro suggested that more C3b was deposited on PspA-negative than on PspA-positive pneumococci. This was observed with and without anticapsular antibody. Furthermore, processing of the α chain of C3b was reduced in the presence of PspA. We propose that PspA exerts its virulence function by interfering with deposition of C3b onto pneumococci and/or by inhibiting formation of a fully functional alternative pathway C3 convertase. By blocking recruitment of the alternative pathway, PspA reduces the amount of C3b deposited onto pneumococci, thereby reducing the effectiveness of complement receptor-mediated pathways of clearance.

scholarly journals Pertussis Toxin Improves Immune Responses to a Combined Pneumococcal Antigen and Leads to Enhanced Protection against Streptococcus pneumoniae

2014 ◽  
Vol 21 (7) ◽  
pp. 972-981 ◽  
Author(s):  
Carolina Salcedo-Rivillas ◽  
Anne-Sophie Debrie ◽  
Eliane Namie Miyaji ◽  
Jorge M. C. Ferreira ◽  
Isaías Raw ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Pertussis Toxin ◽  
Protein A ◽  
Passive Immunization ◽  
Surface Protein ◽  
Interleukin 17 ◽  
Adjuvant Activity ◽  
Content Type

ABSTRACTPneumococcal surface protein A (PspA) is a candidate antigen for the composition of protein-based vaccines againstStreptococcus pneumoniae. While searching for efficient adjuvants for PspA-based vaccines, our group has described the potential of combining PspA with the whole-cell pertussis vaccine (wP). When given to mice through the nasal route, a formulation composed of PspA from clade 5 (PspA5) and wP (PspA5-wP) induced high levels of antibodies and protection against challenges with different pneumococcal strains. PspA5-wP also induced the secretion of interleukin 17 (IL-17) by splenocytes and the infiltration of leukocytes in the lungs after challenge. Here, we show that protection against a pneumococcal invasive challenge was completely abrogated in μMT−/−mice, which are deficient in the maturation of B cells, illustrating the importance of antibodies in the survival elicited by the PspA5-wP vaccine. Moreover, passive immunization showed that IgG purified from the sera of mice immunized with PspA5-wP conferred significant protection to naive mice, whereas the respective F(ab′)2did not. Additionally,in vivodepletion of complement abolished protection against the pneumococcal challenge. The combination of PspA5 with wild-type or mutantBordetella pertussisstrains or with purified components showed that the pertussis toxin (PT)-containing formulations induced the highest levels of antibodies and protection. This suggests that the adjuvant activity of wP in the PspA5 model is mediated at least in part by PT. The sera from mice immunized with such formulations displayed high IgG binding and induction of complement deposition on the pneumococcal surfacein vitro, which is consistent with thein vivoresults.

scholarly journals Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through ‘reverse phenotyping’

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
David S. Fischer ◽  
Meshal Ansari ◽  
Karolin I. Wagner ◽  
Sebastian Jarosch ◽  
Yiqi Huang ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Rna Sequencing ◽  
Ex Vivo ◽  
Severe Disease ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Single Cell Rna Sequencing

AbstractThe in vivo phenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells require in vitro antigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we use single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. To do so, we induce transcriptional shifts by antigenic stimulation in vitro and take advantage of natural T cell receptor (TCR) sequences of clonally expanded T cells as barcodes for ‘reverse phenotyping’. This allows identification of SARS-CoV-2-reactive TCRs and reveals phenotypic effects introduced by antigen-specific stimulation. We characterize transcriptional signatures of currently and previously activated SARS-CoV-2-reactive T cells, and show correspondence with phenotypes of T cells from the respiratory tract of patients with severe disease in the presence or absence of virus in independent cohorts. Reverse phenotyping is a powerful tool to provide an integrated insight into cellular states of SARS-CoV-2-reactive T cells across tissues and activation states.

scholarly journals TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo

2010 ◽  
Vol 207 (8) ◽  
pp. 1701-1711 ◽  
Author(s):  
Rachel A. Gottschalk ◽  
Emily Corse ◽  
James P. Allison
Keyword(s):  
T Cells ◽  
Time Course ◽  
Low Dose ◽  
Cell Receptor ◽  
Peripheral Tolerance ◽  
Ligand Density ◽  
Forkhead Box ◽  
Histocompatibility Complex ◽  
Maximal Induction

T cell receptor (TCR) ligation is required for the extrathymic differentiation of forkhead box p3+ (Foxp3+) regulatory T cells. Several lines of evidence indicate that weak TCR stimulation favors induction of Foxp3 in the periphery; however, it remains to be determined how TCR ligand potency influences this process. We characterized the density and affinity of TCR ligand favorable for Foxp3 induction and found that a low dose of a strong agonist resulted in maximal induction of Foxp3 in vivo. Initial Foxp3 induction by weak agonist peptide could be enhanced by disruption of TCR–peptide major histocompatibility complex (pMHC) interactions or alteration of peptide dose. However, time course experiments revealed that Foxp3-positive cells induced by weak agonist stimulation are deleted, along with their Foxp3-negative counterparts, whereas Foxp3-positive cells induced by low doses of the strong agonist persist. Our results suggest that, together, pMHC ligand potency, density, and duration of TCR interactions define a cumulative quantity of TCR stimulation that determines initial peripheral Foxp3 induction. However, in the persistence of induced Foxp3+ T cells, TCR ligand potency and density are noninterchangeable factors that influence the route to peripheral tolerance.

scholarly journals DNA vaccines expressing pneumococcal surface protein A (PspA) elicit protection levels comparable to recombinant protein

2006 ◽  
Vol 55 (4) ◽  
pp. 375-378 ◽  
Author(s):  
Daniela M. Ferreira ◽  
Eliane N. Miyaji ◽  
Maria Leonor S. Oliveira ◽  
Michelle Darrieux ◽  
Ana Paula M. Arêas ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Recombinant Protein ◽  
Dna Vaccines ◽  
Protein A ◽  
Surface Protein ◽  
Humoral Response ◽  
Cost Effective ◽  
Promising Candidate ◽  
Pneumococcal Surface Protein A ◽  
Antibody Levels

Pneumococcal surface protein A (PspA) is a promising candidate for the development of cost-effective vaccines against Streptococcus pneumoniae. In the present study, BALB/c mice were immunized with DNA vaccine vectors expressing the N-terminal region of PspA. Animals immunized with a vector expressing secreted PspA developed higher levels of antibody than mice immunized with the vector expressing the antigen in the cytosol. However, both immunogens elicited similar levels of protection against intraperitoneal challenge. Furthermore, immunization with exactly the same fragment in the form of a recombinant protein, with aluminium hydroxide as an adjuvant, elicited even higher antibody levels, but this increased humoral response did not correlate with enhanced protection. These results show that DNA vaccines expressing PspA are able to elicit protection levels comparable to recombinant protein, even though total anti-PspA IgG response is considerably lower.

scholarly journals In Vivo Selection of T-Cell Receptor Junctional Region Sequences by HLA-A2 Human T-Cell Lymphotropic Virus Type 1 Tax11-19 Peptide Complexes

2001 ◽  
Vol 75 (2) ◽  
pp. 1065-1071 ◽  
Author(s):  
Mineki Saito ◽  
Graham P. Taylor ◽  
Akiko Saito ◽  
Yoshitaka Furukawa ◽  
Koichiro Usuku ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Virus Type ◽  
Cell Receptor ◽  
Antigen Specificity ◽  
Human T Cell ◽  
Cdr3 Region

ABSTRACT Using HLA-peptide tetrameric complexes, we isolated human T-cell lymphotrophic virus type 1 Tax peptide-specific CD8+ T cells ex vivo. Antigen-specific amino acid motifs were identified in the T-cell receptor Vβ CDR3 region of clonally expanded CD8+ T cells. This result directly confirms the importance of the CDR3 region in determining the antigen specificity in vivo.

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