T-Cell-Independent Immune Responses Do Not Require Cxc Ligand 13-Mediated B1 Cell Migration

ABSTRACT The dynamic movement of B cells increases the probability of encountering specific antigen and facilitates cell-cell interactions required for mounting a rapid antibody response. B1a and B1b cells are enriched in the coelomic cavity, contribute to T-cell-independent (TI) antibody responses, and increase in number upon antigen exposure. B1 cell movement is largely governed by Cxc ligand 13 (Cxcl13), and mice deficient in this chemokine have a severe reduction in peritoneal B1 cells. In this study, we examined the role of Cxcl13-dependent B cell migration using Borrelia hermsii infection or intraperitoneal immunization with pneumococcal polysaccharide or 4-hydroxy-3-nitrophenyl-acetyl (NP)-Ficoll, all of which induce robust antibody responses from B1b cells. Surprisingly, we found that antibody responses to B. hermsii or to FhbA, an antigenic target of B1b cells, and the resolution of bacteremia were indistinguishable between wild-type and Cxcl13 −/− mice. Importantly, we did not observe an expansion of peritoneal B1b cell numbers in Cxcl13 −/− mice. Nonetheless, mice that had resolved infection were resistant to reinfection, indicating that the peritoneal B1b cell reservoir is not required for controlling B. hermsii. Furthermore, despite a reduced peritoneal B1b compartment, immunization with pneumococcal polysaccharide vaccine yielded comparable antigen-specific antibody responses in wild-type and Cxcl13 −/− mice and conferred protection against Streptococcus pneumoniae. Likewise, immunization with NP-Ficoll elicited similar antibody responses in wild-type and Cxcl13 −/− mice. These data demonstrate that homing of B1 cells into the coelomic cavity is not a requirement for generating protective TI antibody responses, even when antigen is initially localized to this anatomical compartment.

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Mechanism of Reduced T-Cell Effector Functions and Class-Switched Antibody Responses to Herpes Simplex Virus Type 2 in the Absence of B7 Costimulation

Journal of Virology ◽

10.1128/jvi.77.4.2426-2435.2003 ◽

2003 ◽

Vol 77 (4) ◽

pp. 2426-2435 ◽

Cited By ~ 21

Author(s):

Lydia G. Thebeau ◽

Lynda A. Morrison

Keyword(s):

T Cells ◽

T Cell ◽

Cytokine Production ◽

Antibody Responses ◽

Wild Type ◽

Effector Functions ◽

Lymphocyte Activity ◽

Ifn Γ ◽

Simplex Virus

ABSTRACT T-cell costimulation molecules B7-1 and B7-2 play an important role in activation of T cells to cytolytic effector function and production of cytokines. Interaction with B7 also causes T cells to upregulate surface molecules, such as CD40L, that effectively stimulate antibody responses in conjunction with cytokines. We have shown that mice lacking both B7-1 and B7-2 (B7KO mice), when infected intravaginally with virulent herpes simplex virus type 2 (HSV-2), developed more severe disease and higher mortality than their wild-type counterparts. We have now investigated the effects of B7 costimulation deficiency on induction of immune responses to HSV-2 infection of the genital tract. Fewer gamma interferon (IFN-γ)-producing T cells were present in the genital lymph nodes of B7KO mice compared to wild-type mice, either acutely after primary infection or in recall responses. Less IFN-γ and especially interleukin-10 were produced by B7KO mice, and cytolytic T-lymphocyte activity was also attenuated. Reduced expression of CD25 on CD4+ T cells after infection of B7KO mice was consistent with deficits in T-cell activation to effector functions. Although HSV-specific immunoglobulin M (IgM) titers were comparable for both B7KO mice and wild-type mice, B7KO mice had significant deficits in HSV-specific serum IgG responses, with markedly reduced levels of IgG2a and IgG1. In addition, significantly less IgG was detected in the vaginal secretions of B7KO mice than in those from wild-type mice. CD4+ T-cell expression of CD40L was depressed in B7KO mice in vivo and in vitro. Together with reduced cytokine production, these results suggest a mechanism for decreased IgG class switching or production. Thus, in the absence of B7 costimulation, naïve T cells fail to undergo proper activation in response to HSV-2, which limits T-cell cytokine production, cytotoxic T lymphocyte activity, and provision of help for class-switched antibody responses.

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Wild-Type p53 Attenuates Cancer Cell Motility by Inducing Growth Differentiation Factor-15 Expression

Endocrinology ◽

10.1210/en.2011-0059 ◽

2011 ◽

Vol 152 (8) ◽

pp. 2987-2995 ◽

Cited By ~ 20

Author(s):

Jung-Chien Cheng ◽

Hsun-Ming Chang ◽

Peter C. K. Leung

Keyword(s):

Cell Migration ◽

Cell Motility ◽

Cancer Cell ◽

Cell Movement ◽

Migration And Invasion ◽

Wild Type ◽

Growth Differentiation Factor 15 ◽

Cancer Cell Motility ◽

Differentiation Factor ◽

Wild Type P53

A major function of the p53 tumor suppressor is the regulation of the cell cycle and apoptosis. In addition to its well-documented functions in malignant cancer cells, p53 can also regulate cell migration and invasion, which contribute to metastasis. Growth differentiation factor-15 (GDF-15), a member of the TGF-β superfamily, has been shown to be a downstream target of p53 and is associated with diverse human diseases and cancer progression. In this study, we examined the potential role of GDF-15 in p53-regulated cancer cell motility. We show that overexpression of wild-type p53 in two highly invasive p53-null human cancer cell lines, SKOV3 and PC3, attenuated cell migration and the movement through Matrigel. Using wild-type p53 and DNA-binding-deficient p53 mutants, we found that the transcriptional activity of p53 is required in the induction of GDF-15 expression. Cell movement through uncoated and Matrigel-coated transwell decreased in response to treatment with recombinant GDF-15, whereas the cell proliferation was not affected by GDF-15 treatment. Moreover, the induction of GDF-15 expression and secretion by p53 and the reduction in cell movement through Matrigel were diminished by treatment with GDF-15 small interfering RNA. This study demonstrates a mechanism by which p53 attenuates cancer cell motility through GDF-15 expression. In addition, our results indicate that GDF-15 mediates the functions of p53 by autocrine/paracrine action.

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B cell-intrinsic requirement for WNK1 kinase in T cell-dependent antibody responses

10.1101/2021.09.09.459588 ◽

2021 ◽

Author(s):

Darryl Hayward ◽

Lesley Vanes ◽

Stefanie Wissmann ◽

Sujana Sivapatham ◽

Harald Hartweger ◽

...

Keyword(s):

T Cells ◽

Cell Migration ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Plasma Cells ◽

Antibody Responses ◽

B Cell Activation

AbstractMigration and adhesion play critical roles in B cells, regulating recirculation between lymphoid organs, migration within lymphoid tissue and interaction with CD4+ T cells. However, there is limited knowledge of how B cells integrate chemokine receptor and integrin signaling with B cell activation to generate efficient humoral responses. Here we show that the WNK1 kinase, a regulator of migration and adhesion, is essential in B cells for T-dependent antibody responses. We demonstrate that WNK1 transduces signals from the BCR, CXCR5 and CD40, and using intravital imaging we show that WNK1 regulates migration of naive and activated B cells, and their interactions with T cells. Unexpectedly, we show that WNK1 is required for BCR- and CD40-induced proliferation, acting through the OXSR1 and STK39 kinases, and for efficient B cell-T cell collaboration in vivo. Thus, WNK1 is critical for humoral immune responses, by regulating B cell migration, adhesion and T cell-dependent activation.SummaryThe WNK1 kinase is essential in B cells for T-dependent antibody responses because it is activated by signaling from BCR, CXCR5 and CD40 and regulates B cell migration, adhesion, T-dependent activation, and differentiation into germinal center B cells and plasma cells.

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Influenza H1 Mosaic Hemagglutinin Vaccine Induces Broad Immunity and Protection in Mice

Vaccines ◽

10.3390/vaccines7040195 ◽

2019 ◽

Vol 7 (4) ◽

pp. 195 ◽

Cited By ~ 1

Author(s):

Brigette N. Corder ◽

Brianna L. Bullard ◽

Jennifer L. DeBeauchamp ◽

Natalia A. Ilyushina ◽

Richard J. Webby ◽

...

Keyword(s):

T Cell ◽

Influenza Vaccine ◽

Protective Immunity ◽

Influenza A ◽

T Cell Responses ◽

Antibody Responses ◽

T Cell Epitopes ◽

Wild Type ◽

Cell Responses ◽

Universal Influenza Vaccine

Annually, influenza A virus (IAV) infects ~5–10% of adults and 20–30% of children worldwide. The primary resource to protect against infection is by vaccination. However, vaccination only induces strain-specific and transient immunity. Vaccine strategies that induce cross-protective immunity against the broad diversity of IAV are needed. Here we developed and tested a novel mosaic H1 HA immunogen. The mosaic immunogen was optimized in silico to include the most potential B and T cell epitopes (PBTE) across a diverse population of human H1 IAV. Phylogenetic analysis showed that the mosaic HA localizes towards the non-pandemic 2009 strains which encompasses the broadest diversity in the H1 IAV population. We compared the mosaic H1 immunogen to wild-type HA immunogens and the commercial inactivated influenza vaccine, Fluzone. When analyzed by ELISA, the mosaic immunogen induced stronger antibody responses against all four diverse H1 HA proteins. When analyzing T cell responses, again the mosaic immunogen induced stronger cellular immunity against all 4 diverse HA strains. Not only was the magnitude of T cell responses strongest in mosaic immunized mice, the number of epitopes recognized was also greater. The mosaic vaccinated mice showed strong cross-protection against challenges with three divergent IAV strains. These data show that the mosaic immunogen induces strong cross-protective immunity and should be investigated further as a universal influenza vaccine.

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PLCβ Is Critical for T-Cell Chemotaxis In Vivo.

Blood ◽

10.1182/blood.v104.11.2650.2650 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2650-2650

Author(s):

Tami L. Bach ◽

Qing-Min Chen ◽

Martha S. Jordan ◽

John K. Choi ◽

Dianqing Wu ◽

...

Keyword(s):

T Cells ◽

Cell Migration ◽

T Cell ◽

Chronic Inflammation ◽

Critical Role ◽

Neutrophil Chemotaxis ◽

Wild Type ◽

T Cell Migration

Abstract Chemokines acting through G-protein coupled receptors play an essential role in both the immune and inflammatory responses. Phosphatidylinositol 3-kinase (PI3K) and phospholipase C (PLC) are two distinct signaling molecules that have been proposed as potential candidates in the regulation of this process. Studies with knockout mice have demonstrated a critical role for PI3Kγ, but not PLCβ, in Gαi-coupled receptor-mediated neutrophil chemotaxis. We compared the chemotactic response of peripheral T-cells derived from wild type mice with mice containing loss-of-function mutations of either PI3Kγ, or both of the two predominant lymphocyte PLCβ isoforms (PLCβ2 and PLCβ3). In contrast to neutrophils, loss of PI3Kγ did not significantly impair T-cell migration in vitro, although PI3K pharmacologic inhibitor experiments suggest that another isoform of this enzyme might contribute to T-cell migration. However, loss of PLCβ2β3 decreased chemokine-stimulated T-cell migration in vitro. Chelation of intracellular calcium by BAPTA-AM and Quin-2 AM decreased the chemotactic response of wild type lymphocytes, but pharmacologic inhibition of PKC isoforms by GF109203x did not impair T-cell migration. This suggests that the T-cell migration defect seen in the PLCβ2β3-null T-cells may be due to an impaired ability to increase the cytoplasmic calcium concentration, while there appears to be little requirement for PKC activity. Indeed, SDF-1α-induced calcium efflux was not detected in the PLCβ2β3-null lymphocytes. Compared to fluorescently labeled wild type T-cells, labeled PLCβ2β3 knockout T-cells migrated less efficiently into secondary lymphoid organs of recipient mice. This demonstrates that PLCβ is also required for migration in vivo. PLCβ2β3-null mice develop spontaneous skin ulcers starting around 3 months of age. Histological examination of the lesions revealed a dense inflammatory infiltrate composed of neutrophils, macrophages, and plasma cells, consistent with acute and chronic inflammation. Remarkably, lymphocytes, typical of chronic inflammation, were rare to absent by histology and by paraffin immunohistochemistry for CD3, also consistent with an in vivo migratory defect of T-cells. These results show that phospholipid second messengers generated by PLCβ and isoforms of PI3K, other than PI3Kγ, play a critical role in lymphocyte chemotaxis. Collectively, our data demonstrate that although PLCβ-mediated signaling plays no role in neutrophil chemotaxis, it makes a substantial contribution to this process within T-lymphocytes.

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An expanding network of cytoskeletal defects

Blood ◽

10.1182/blood-2018-10-878603 ◽

2018 ◽

Vol 132 (22) ◽

pp. 2316-2317 ◽

Cited By ~ 1

Author(s):

Michael D. Keller

Keyword(s):

Cell Migration ◽

T Cell ◽

Combined Immunodeficiency ◽

Wild Type ◽

Immune Synapse ◽

T Cell Migration

In this issue of Blood, Brigida et al1 demonstrate that null mutations in ARPC1B result in combined immunodeficiency because of defects in T-cell migration, lymphoproliferation, and formation of the immune synapse, and further show that these abnormalities may be rescued by transduction of wild-type ARPC1B.

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CD4 T Cell Memory and Antibody Responses Directed against the Pneumococcal Histidine Triad Proteins PhtD and PhtE following Nasopharyngeal Colonization and Immunization and Their Role in Protection against Pneumococcal Colonization in Mice

Infection and Immunity ◽

10.1128/iai.00313-13 ◽

2013 ◽

Vol 81 (10) ◽

pp. 3781-3792 ◽

Cited By ~ 21

Author(s):

M. N. Khan ◽

M. E. Pichichero

Keyword(s):

T Cell ◽

Serum Antibody ◽

Antibody Responses ◽

Cd4 T Cell ◽

T Cell Memory ◽

Immune Memory ◽

Wild Type ◽

Cell Memory ◽

Pneumococcal Colonization ◽

Isogenic Mutants

ABSTRACTThe present study was undertaken to understand the role of vaccine candidates PhtD and PhtE in pneumococcal nasopharyngeal (NP) colonization, their ability to induce CD4 T cell memory and antibody responses following primary NP colonization, and their contribution to protection against secondary pneumococcal colonization in mice. The study was also aimed at understanding the potential of immunization with PhtD and PhtE in eliciting qualitative CD4 T cell memory responses and protection against pneumococcal NP colonization in mice. PhtD and PhtE isogenic mutants in a TIGR4 background (TIGR4 ΔPhtD and TIGR4 ΔPhtE) were constructed and found to have a significantly reduced colonization density over time in the nasopharynges of mice compared to those of mice colonized with wild-type TIGR4. Mice with primary colonization by wild-type TIGR4, TIGR4 ΔPhtD, or TIGR4 ΔPhtE were protected against secondary colonization by wild-type TIGR4; nonetheless, the clearance of secondary colonization was slower in mice with primary colonization by either TIGR4 ΔPhtD or TIGR4 ΔPhtE than in mice with primary colonization by wild-type TIGR4. Colonization was found to be an immunizing event for PhtD and PhtE antigens (antibody response); however, we failed to detect any antigen (PhtD or PhtE)-specific CD4 T cell responses in any of the colonized groups of mice. Intranasal immunization with either PhtD or PhtE protein generated robust serum antibody and CD4 Th1-biased immune memory and conferred protection against pneumococcal colonization in mice. We conclude that PhtD and PhtE show promise as components in next-generation pneumococcal vaccine formulations.

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Antigen-driven C–C Chemokine-mediated HIV-1 Suppression by CD4+ T Cells from Exposed Uninfected Individuals Expressing the Wild-type CCR-5 Allele

Journal of Experimental Medicine ◽

10.1084/jem.186.3.455 ◽

1997 ◽

Vol 186 (3) ◽

pp. 455-460 ◽

Cited By ~ 82

Author(s):

Lucinda Furci ◽

Gabriella Scarlatti ◽

Samuele Burastero ◽

Giuseppe Tambussi ◽

Claudia Colognesi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Vaccine Development ◽

Specific Antigen ◽

T Cell Response ◽

Wild Type ◽

Cell Immunity ◽

Base Pair Deletion ◽

Exposed Uninfected ◽

Hiv 1

Despite repeated exposure to HIV-1, certain individuals remain persistently uninfected. Such exposed uninfected (EU) people show evidence of HIV-1–specific T cell immunity and, in rare cases, selective resistance to infection by macrophage-tropic strains of HIV-1. The latter has been associated with a 32–base pair deletion in the C–C chemokine receptor gene CCR-5, the major coreceptor of macrophage-tropic strains of HIV-1. We have undertaken an analysis of the HIV-specific T cell responses in 12 EU individuals who were either homozygous for the wild-type CCR-5 allele or heterozygous for the deletion allele (CCR-5Δ32). We have found evidence of an oligoclonal T cell response mediated by helper T cells specific for a conserved region of the HIV-1 envelope. These cells produce very high levels of C–C chemokines when stimulated by the specific antigen and suppress selectively the replication of macrophage-tropic, but not T cell–tropic, strains of HIV-1. These chemokine-producing helper cells may be part of a protective immune response that could be potentially exploited for vaccine development.

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Age-related heterogeneity in Neutralising antibody responses to SARS-CoV-2 following BNT162b2 vaccination

10.1101/2021.02.03.21251054 ◽

2021 ◽

Cited By ~ 1

Author(s):

Dami Collier ◽

Isabella Ferreira ◽

Rawlings Datir ◽

Bo Meng ◽

Laura Bergamaschi ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Somatic Hypermutation ◽

Geometric Mean ◽

T Cell Response ◽

Antibody Responses ◽

High Risk Population ◽

Age Group ◽

Wild Type ◽

Dosing Interval

Background Vaccines remain the cornerstone for containing the SARS-CoV-2 pandemic. mRNA vaccines provide protection in clinical trials using a two-dose approach, separated by a three to four week gap. UK policy in 2021 is to extend the dosing interval from three to twelve weeks and other countries are likely to follow suit given the demand for mRNA vaccines and ongoing uncontrolled transmission. There is a paucity of data in the elderly, even though these individuals are the first to receive vaccines due to risk of severe disease. Here we assessed real world immune responses following vaccination with mRNA-based vaccine BNT162b2. Methods: We did a prospective cohort study of 101 individuals presenting for first dose vaccination, with a subset having the second dose. Following the first and second doses of the BNT162b2 vaccine, we measured binding antibody (IgA, IgG and IgG1-4) responses to Spike and Spike RBD, serum neutralising antibody responses to wild type (Wuhan-1 with D614G) and the B.1.1.7 Spike variant using a lentiviral pseudotyping system. We also analysed B cell repertoires and autoantibodies were measured. We measured spike specific IFNgamma; and IL-2 T cell responses and CMV serostatus. We correlated age with immune responses and compared responses after the first and second doses. Results Median age was 81 years amongst 101 participants after the first dose of the BNT162b2 vaccine. Geometric mean neutralisation titres in participants over 80 years old after the first dose were lower than in younger individuals [83.4 (95% CI 52.0-133.7) vs 46.6 (95% CI 33.5-64.8) p 0.01]. A lower proportion of participants 80 years and older achieved adequate neutralisation titre of >1:20 for 50% neutralisation as compared to those under 80 (21% vs 51%, p 0.003). Binding IgG responses correlated with neutralisation. Sera from participants in both age groups showed significantly lower neutralisation potency against B.1.1.7 Spike pseudotyped viruses as compared to wild type. The adjusted ORs for inadequate neutralisation in the 80 years and above age group were 3.7 (95% CI 1.2-11.2) and 4.4 (95% CI 1.5-12.6) against wild type and B.1.1.7 pseudotyped viruses. We observed a trend towards lower somatic hypermutation in participants with suboptimal neutralisation, and elderly participants demonstrated clear reduction in class switched somatic hypermutation, driven by the IgA1/2 isotype. SARS-CoV-2 Spike specific T- cell IFNgamma; and IL-2 responses were impaired in the older age group after 1 dose and although IFN𝛾 increased between vaccine doses, IL-2 responses did not significantly increase. Conclusions There was a significantly higher risk of suboptimal neutralising antibody and T cell response following first dose vaccination with BNT162b2 in half of participants above the age of 80, persisting up to 12 weeks. We caution against extending the dosing interval in this high risk population where B.1.1.7 and other variants of concern are circulating.

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Efficient B Cell Responses to Borrelia hermsii Infection Depend on BAFF and BAFFR but Not TACI

Infection and Immunity ◽

10.1128/iai.01147-13 ◽

2013 ◽

Vol 82 (1) ◽

pp. 453-459 ◽

Cited By ~ 10

Author(s):

Gregory S. Dickinson ◽

Guizhi Sun ◽

Richard J. Bram ◽

Kishore R. Alugupalli

Keyword(s):

T Cell ◽

B Cell ◽

Cell Subset ◽

Surface Expression ◽

Antibody Responses ◽

Borrelia Hermsii ◽

Content Type ◽

B Cell Homeostasis ◽

And Function ◽

Type 3

ABSTRACTT cell-independent antibody responses develop rapidly, within 3 to 4 days, and are critical for preventing blood-borne pathogens from evolving into life-threatening infections. The interaction of BAFF, also known as BLyS, with its receptors BAFFR and TACI on B cells is critical for B cell homeostasis and function. Using a synthetic polysaccharide antigen, it has previously been shown that TACI is critical for T cell-independent antibody responses. To examine the role of BAFFR and TACI in T cell-independent antibody responses to an active infection, we utilized theBorrelia hermsiiinfection system. In this infection system, T cell-independent responses mediated by the B1b cell subset are critical for controlling bacteremia. We found that B1b cells express BAFFR and TACI and that the surface expression of both receptors is upregulated on B1b cells following exposure to wholeB. hermsiicells. Surprisingly, we found that TACI−/−mice are not impaired either in specific antibody responses toB. hermsiior in controllingB. hermsiibacteremia. In contrast, TACI-deficient mice immunized with heat-killed type 3 serotype pneumococcus cells are impaired in generating pneumococcal polysaccharide-specific responses and succumb to challenge with live type 3 serotype pneumococcus, indicating that TACI is required for T cell-independent antibody responses to bacterial-associated polysaccharides. Although we have found that TACI is dispensable for controllingB. hermsiiinfection, mice deficient in BAFFR or BAFF exhibit impairment inB. hermsii-specific IgM responses and clearance of bacteremia. Collectively, these data indicate a disparity in the roles for TACI and BAFFR in primary T cell-independent antibody responses to bacterial pathogens.

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