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Bisphosphonate effect on murine whole draining lymph nodes before and 8 hours after VSV infection

ABSTRACT: Bisphosphonates are a class of drugs that are widely used to inhibit loss of bone mass in patients. We show that the administration of clinically relevant doses of bisphosphonates in mice increases antibody responses to live and inactive viruses, proteins, haptens and existing commercial vaccine formulations. Bisphosphonates exert this adjuvant-like activity in the absence of CD4+ and γδ T cells, neutrophils or dendritic cells and their effect does not rely on local macrophage depletion nor does it depend upon Toll-like receptor signaling or the inflammasome. Rather, bisphosphonates target directly B cells and enhance B cell expansion and antibody production upon antigen encounter. These data establish bisphosphonates as a novel class of adjuvants that boost humoral immune responses. Of note, gene-expression profile analysis shows that bisphosphonate treatment up-regulates a number of B cell-specific transcripts and gene sets associated with B cell function, suggesting that bisphosphonates might directly target B cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE50403 | GEO | 2013/08/29

SECONDARY ACCESSION(S): PRJNA217414

REPOSITORIES: GEO

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Bisphosphonate effect on murine whole draining lymph nodes before and 8 hours after VSV infection

Project description:Bisphosphonates are a class of drugs that are widely used to inhibit loss of bone mass in patients. We show that the administration of clinically relevant doses of bisphosphonates in mice increases antibody responses to live and inactive viruses, proteins, haptens and existing commercial vaccine formulations. Bisphosphonates exert this adjuvant-like activity in the absence of CD4+ and γδ T cells, neutrophils or dendritic cells and their effect does not rely on local macrophage depletion nor does it depend upon Toll-like receptor signaling or the inflammasome. Rather, bisphosphonates target directly B cells and enhance B cell expansion and antibody production upon antigen encounter. These data establish bisphosphonates as a novel class of adjuvants that boost humoral immune responses. Of note, gene-expression profile analysis shows that bisphosphonate treatment up-regulates a number of B cell-specific transcripts and gene sets associated with B cell function, suggesting that bisphosphonates might directly target B cells. C57Bl/6 mice received intrafoodpad injections of Clodronate (CLD, 2mg) or vehicle control (PBS) 3 and 1 day prior to infection with VSV serotype Indiana in the same footpad. Popliteal lymph nodes were harvested immediately before or 8 hours after the infection. Total RNA was extracted and prepared for hybridization on Affymetrix microarrays.

2013-08-29 | E-GEOD-50403 | biostudies-arrayexpress

MHC class II inhibits the generation of IL-17A+ Vγ6 γδ T cells in the thymus at perinatal stage

Project description:TCR γ chain loci of mice have seven variable (Vγ) gene segments (Vγ1, Vγ2, Vγ3, Vγ4, Vγ5, Vγ6, and Vγ7) using the Heilig and Tonegawa nomenclature. Vγ6+ γδ T cells, which develop in the thymus at the perinatal stage, are distributed within the mucosal tissues in the periphery. Vγ6+ γδ T cells are exclusive interleukin (IL)-17 producers among γδ T cells, and Vγ6+ IL-17A+ γδ T (γδT17) cells play important roles in protection against microbial infection and in the pathogenesis of inflammatory diseases, such as colitis and autoimmune diseases. We have previously reported that γδT17 cells develop from the CD4–CD8– (DN)2b stage in the thymus at the prenatal stage in a Bcl11b-dependent manner. However, details of the development of Vγ6+ γδT17 cells remain obscure. To analyze Vγ6+ γδ T cells in detail, we recently developed a monoclonal antibody (mAb; termed 1C10-1F7) specific to mouse Vg6 chain. Use of this mAb revealed that Vγ6+ γδ T cells in 0-day-old thymus were co-localized with medullary thymic epithelial cells (mTECs), which regulate T cell tolerance by self-antigen presentation using major histocompatibility complex (MHC) class II. Here, we report that MHC class II in the thymus inhibits the generation of Vγ6+ γδT17 cells.

2022-08-01 | GSE180320 | GEO

RNA sequencing of gamma-delta T cell subsets from young and old mice

Project description:Organismal ageing is associated with loss of immune function and higher incidence of cancer. Whether the γδ T cell pool changes upon organismal ageing is not known. In this study we have characterized γδ T cells in peripheral lymph nodes from old and young mice. We found that the γδ T cell pool is severely altered in old mice. The IL-17 producing γδ lineage becomes dominating while IFN-γ producing γδ1 T cells are declining. γδTCR sequencing revealed no collapse in diversity but oligoclonal expansions in Vγ4 γδ17 subsets. Pro-tumourigenic invariant Vγ6 cells are present only in aged lymph nodes, represent the majority of γδ T cells in the tumour, and are associated with faster tumour progression.

2019-05-22 | E-MTAB-7178 | biostudies-arrayexpress

Expression data from draining lymph node and muscle of mice immunised with AS03 or PBS

Project description:The oil-in-water emulsion Adjuvant System 03 (AS03) is one of the few adjuvants used in licensed vaccines. AS03 induces a local and transient inflammatory response that contribute to its adjuvant effect. This data provides a more comprehensive analysis of early gene expression both at the injection site and in the draining lymph node 2, 4 or 6 hours after immunisation with AS03.

2018-06-26 | E-MTAB-6632 | biostudies-arrayexpress

Expression data from draining lymph node of mice immunized with AS01 or its components

Project description:Immunization with adjuvanted antigen results in coordinate changes in gene expression. Combination adjuvants exploit the interplay between different immunostimulants to promote immune response to vaccination. The Adjuvant System 01 (AS01) is a liposome-based combination adjuvant which contains two immunostimulants, MPL and QS-21 Here, we assess the contribution of the components of AS01 on its immunogenicity by comparing the transcriptional response induced in the draining lymph node by AS01, MPL and QS-21 at 2,4 or 6h after intramuscolar (i.m.) immunization

2017-08-31 | GSE98322 | GEO

TCR-Vγδ usage distinguishes pro- and anti-tumor intestinal γδ T cell subsets

Project description:γδ T cells represent a substantial fraction of intestinal lymphocytes at homeostasis, but also constitute a major lymphocyte population infiltrating colorectal cancers (CRC), albeit their role in CRC remains unclear. Using human CRC samples and murine CRC models, we found that most γδ T cells in pre- or non-tumor colon exhibit cytotoxic markers while tumor-infiltrating γδ T cells express a pro-tumorigenic profile. These contrasting T cell profiles were associated with distinct TCR-Vγδ gene-usage in both mice and humans. Complementary intersectional genetics and antibody-dependent strategies targeting murine γδ T cells enriched in the epithelium at steady state led to heightened tumor development, while targeting γδ subsets that accumulate during CRC resulted in reduced tumor growth. Our results uncover pro- and anti-tumor roles for γδ T cell subsets.

2022-06-14 | GSE205720 | GEO

Vγ6+ γδ T cells play a critical role in protection against infection by Escherichia coli

Project description:γδ T cells producing interleukin 17A (IL-17A), which are mainly Vγ4 and Vγ6 subsets, are involved in protection against infection by extracellular bacteria. Using a new Vγ6-specific monoclonal antibody (mAb) (1C10-1F7) which we recently developed, we found that IL-17A+ Vγ6+ γδ T cells increased predominantly in the peritoneal cavity compared with IL-17A+ Vγ4+ γδ T cells during intraperitoneal Escherichia coli infection. The number of IL-17A+ Vγ6+ γδ T cells, which rapidly became CD69+ from CD69-, peaked at 12 h after infection. In vivo treatment with 1C10-1F7 mAb significantly inhibited the accumulation of neutrophils and hampered the resolution of E. coli infection. These results suggest that rapid activation of IL-17A+ Vγ6+ γδ T cells contributed to host defence against E. coli infection.

2020-02-28 | GSE144617 | GEO

Long-lived central memory gamma delta T cells confer protection against murine cytomegalovirus reinfection

Project description:The involvement of γδ TCR-bearing lymphocytes in immunological memory has gained increasing interest due to their functional duality between adaptive and innate immunity. γδ T effector memory (TEM) and central memory (TCM) subsets have been identified, but their respective roles in memory responses are poorly understood. In the present study, we used subsequent mouse cytomegalovirus (MCMV) infections of αβ T cell deficient mice in order to analyze the memory potential of γδ T cells. As for CMV-specific αβ T cells, MCMV induced the accumulation of cytolytic, KLRG1+CX3CR1+ γδ TEM that principally localized in infected organ vasculature. Typifying T cell memory, γδ T cell expansion in organs and blood was higher and more efficient after secondary viral challenge than after primary infection. Viral control upon MCMV reinfection was prevented when masking γδ T-cell receptor, and was associated with a preferential amplification of private and unfocused TCR δ chain repertoire composed of a combination of clonotypes expanded post-primary infection and, more unexpectedly, of novel expanded clonotypes. Finally, long-term-primed γδ TCM cells, but not γδ TEM cells, protected T cell-deficient hosts against MCMV-induced death upon adoptive transfer, probably through their ability to survive and to generate TEM in the recipient host. This better survival potential of TCM cells was confirmed by a detailed scRNASeq analysis of these two γδ T cell subsets which also revealed their similarity to classically adaptive αβ CD8 T cells. Overall, our study uncovered memory properties of long-lived TCM γδ T cells that confer protection in a chronic infection, highlighting the interest of this T cell subset in vaccination approaches.

2024-07-25 | GSE269394 | GEO

Gene expression signature in ablated IL-38 PyMT tumors dependent on T cells

Project description:We studied the impact of IL-38 neutralization on tumor immune control in PyMT mammary carcinoma mouse model via γδ T cells. To that end, whole transcriptome profile of PyMT tumors upon in vivo IL-38 neutralization and γδ-TCR blockage were generate via next generation mRNA sequencing on a NextSeq 2000 sequencer.

2024-08-16 | GSE239398 | GEO

Breast cancer stem cell-derived tumors escape from γδ T cell immunosurveillance in vivo by modulating γδ T cell ligands

Project description:Triple negative breast cancer (TNBC) lacks targeted therapy options. TNBC is enriched in breast cancer stem cells (BCSCs), which play a key role in metastasis, chemoresistance, relapse and mortality. γδ T cells hold great potential in immunotherapy against cancer, and might be an alternative to target TNBC. γδ T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor sensing, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. We show that patient derived triple negative BCSCs are efficiently recognized and killed by ex vivo expanded γδ T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to γδ T cell immunotherapy. Mechanistically, we unraveled concerted differentiation and immune escape: xenografted BCSCs lost stemness, expression of γδ T cell ligands, adhesion molecules and pAgs, thereby evading immune recognition by γδ T cells. Indeed, neither pro-migratory engineered γδ T cells, nor anti-PD 1 checkpoint blockade significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the γδ T cells, and could be pharmacologically reverted by Zoledronate or IFN-α treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.

2023-07-20 | PXD039463 | Pride

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