γδ T Cells Differentially Regulate Bone Loss in Periodontitis Models

2021 ◽  
pp. 002203452110428
Author(s):  
O. Barel ◽  
Y. Aizenbud ◽  
Y. Tabib ◽  
Y. Jaber ◽  
A. Leibovich ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bone Loss ◽  
Immune Responses ◽  
Alveolar Bone ◽  
Γδ T Cells ◽  
Oral Infection ◽  
Alveolar Bone Loss ◽  
Infection Model ◽  
The Impact

γδ T cells are nonclassical T lymphocytes representing the major T-cell population at epithelial barriers. In the gingiva, γδ T cells are enriched in epithelial regions adjacent to the biofilm and are considered to regulate local immunity to maintain host-biofilm homeostatic interactions. This delicate balance is often disrupted resulting in the development of periodontitis. Previous studies in mice lacking γδ T cells from birth ( Tcrd-/- mice) examined the impact of these cells on ligature-induced periodontitis. Data obtained from those studies proposed either a protective effect or no impact to γδ T cells in this setting. Here, we addressed the role of γδ T cells in periodontitis using the recently developed Tcrd-GDL mice, enabling temporal ablation of γδ T cells. Specifically, the impact of γδ T cells during periodontitis was examined in 2 modalities: the ligature model and the oral infection model in which the pathogen Porphyromonas gingivalis was administrated via successive oral gavages. Ablation of γδ T cells during ligature-induced periodontitis had no impact on innate immune cell recruitment to the ligated gingiva. In addition, the number of osteoclasts and subsequent alveolar bone loss were unaffected. However, γδ T cells play a pathologic role during P. gingivalis infection, and their absence prevented alveolar bone loss. Further analysis revealed that γδ T cells were responsible for the recruitment of neutrophils and monocytes to the gingiva following the exposure to P. gingivalis. γδ T-cell ablation also downregulated osteoclastogenesis and dysregulated long-term immune responses in the gingiva. Collectively, this study demonstrates that whereas γδ T cells are dispensable to periodontitis induced by the ligature model, they play a deleterious role in the oral infection model by facilitating pathogen-induced bone-destructive immune responses. On a broader aspect, this study highlights the complex immunopathologic mechanisms involved in periodontal bone loss.

T-cell contributions to alveolar bone loss in response to oral infection withPorphyromonas gingivalis

2001 ◽  
Vol 59 (4) ◽  
pp. 222-225 ◽  
Author(s):  
Pamela J. Baker ◽  
Jessica Garneau ◽  
Lisa Howe ◽  
Derry C. Roopenian
Keyword(s):  
T Cell ◽  
Bone Loss ◽  
Alveolar Bone ◽  
Oral Infection ◽  
Alveolar Bone Loss

scholarly journals B Cell IgD Deletion Prevents Alveolar Bone Loss Following Murine Oral Infection

2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
Author(s):  
Pamela J. Baker ◽  
Nicole Ryan Boutaugh ◽  
Michaela Tiffany ◽  
Derry C. Roopenian
Keyword(s):  
T Cells ◽  
B Cells ◽  
Bone Loss ◽  
B Cell ◽  
Tooth Loss ◽  
Alveolar Bone ◽  
Oral Infection ◽  
Alveolar Bone Loss ◽  
Oral Colonization ◽  
Deficient Mice

Periodontal disease is one of the most common infectious diseases of humans. Immune responses to infection trigger loss of alveolar bone from the jaw and eventual tooth loss. We investigated the contribution of B cell IgD to alveolar bone loss by comparing the response of B cell normal BALB/cJ mice and IgD deficient BALB/c-Igh-5−/−Jmice to oral infection withPorphyromonas gingivalis, a gram-negative periodontopathic bacterium from humans.P. gingivalis-infected normal mice lost bone. Specific antibody toP. gingivaliswas lower and oral colonization was higher in IgD deficient mice; yet bone loss was completely absent. Infection increased the proportion of CD69+activated B cells and CD4+T cells in immune normal mice compared to IgD deficient mice. These data suggest that IgD is an important mediator of alveolar bone resorption, possibly through antigen-specific coactivation of B cells and CD4+T cells.

scholarly journals CD4+ T Cells and the Proinflammatory Cytokines Gamma Interferon and Interleukin-6 Contribute to Alveolar Bone Loss in Mice

1999 ◽  
Vol 67 (6) ◽  
pp. 2804-2809 ◽  
Author(s):  
Pamela J. Baker ◽  
Mark Dixon ◽  
R. Todd Evans ◽  
Lisa Dufour ◽  
Ellis Johnson ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Bone Loss ◽  
Proinflammatory Cytokines ◽  
Interleukin 6 ◽  
Alveolar Bone ◽  
Adaptive Immune Response ◽  
Oral Infection ◽  
Alveolar Bone Loss ◽  
Adaptive Immune

ABSTRACT In this study, we used a mouse model to examine the role of the adaptive immune response in alveolar bone loss induced by oral infection with the human gram-negative anaerobic bacteriumPorphyromonas gingivalis. Severe combined immunodeficient mice, which lack B and T lymphocytes, exhibited considerably less bone loss than did immunocompetent mice after oral infection, suggesting that lymphocytes contribute to this process. Bone loss after oral infection was decreased in mice deficient in major histocompatibility complex (MHC) class II-responsive CD4+ T cells, but no change in bone loss was observed in mice deficient in MHC class I-responsive CD8+ T cells or NK1+ T cells. Mice lacking the cytokine gamma interferon or interleukin-6 also demonstrated decreased bone loss. These results suggest that the adaptive immune response, and in particular CD4+ T cells and the proinflammatory cytokines that they secrete, are important effectors of bone loss consequent to P. gingivalis oral infection. The studies also reinforce the utility of the mouse oral infection model in dissecting the pathobiology of periodontal disease.

scholarly journals G(-) Anaerobes-Reactive CD4+ T-Cells Trigger RANKL-Mediated Enhanced Alveolar Bone Loss in Diabetic NOD Mice

Diabetes ◽  
2005 ◽  
Vol 54 (5) ◽  
pp. 1477-1486 ◽  
Author(s):  
D. A. Mahamed ◽  
A. Marleau ◽  
M. Alnaeeli ◽  
B. Singh ◽  
X. Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Bone Loss ◽  
Cd4 T Cells ◽  
Alveolar Bone ◽  
Nod Mice ◽  
Alveolar Bone Loss

scholarly journals Microglial response to experimental periodontitis in a murine model of Alzheimer’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Alpdogan Kantarci ◽  
Christina M. Tognoni ◽  
Wael Yaghmoor ◽  
Amin Marghalani ◽  
Danielle Stephens ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Bone Loss ◽  
Alveolar Bone ◽  
Alveolar Bone Loss ◽  
Gm Csf ◽  
Model Of Alzheimer’S Disease ◽  
Double Label ◽  
5Xfad Mice ◽  
The Impact

Abstract Periodontal disease (PD) has been suggested to be a risk factor for Alzheimer’s disease (AD). We tested the impact of ligature-induced PD on 5xFAD mice and WT littermates. At baseline, 5xFAD mice presented significant alveolar bone loss compared to WT mice. After the induction of PD, both WT and 5xFAD mice experienced alveolar bone loss. PD increased the level of Iba1-immunostained microglia in WT mice. In 5xFAD mice, PD increased the level of insoluble Aβ42. The increased level in Iba1 immunostaining that parallels the accumulation of Aβ in 5xFAD mice was not affected by PD except for a decrease in the dentate gyrus. Analysis of double-label fluorescent images showed a decline in Iba1 in the proximity of Aβ plaques in 5xFAD mice with PD compared to those without PD suggesting a PD-induced decrease in plaque-associated microglia (PAM). PD reduced IL-6, MCP-1, GM-CSF, and IFN-γ in brains of WT mice and reduced IL-10 in 5xFAD mice. The data demonstrated that PD increases neuroinflammation in WT mice and disrupts the neuroinflammatory response in 5xFAD mice and suggest that microglia is central to the association between PD and AD.

scholarly journals Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 829 ◽  
Author(s):  
Klaus-Peter Künkele ◽  
Daniela Wesch ◽  
Hans-Heinrich Oberg ◽  
Martin Aichinger ◽  
Verena Supper ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Therapy ◽  
Γδ T Cells ◽  
Host Cells ◽  
Advantages And Disadvantages ◽  
Therapeutic Concepts ◽  
Vγ9vδ2 T Cells ◽  
The Impact

Cancer therapies based on in vivo stimulation, or on adoptive T cell transfer of Vγ9Vδ2 T cells, have been tested in the past decades but have failed to provide consistent clinical efficacy. New, promising concepts such as γδ Chimeric Antigen Receptor (CAR) -T cells and γδ T-cell engagers are currently under preclinical evaluation. Since the impact of factors, such as the relatively low abundance of γδ T cells within tumor tissue is still under investigation, it remains to be shown whether these effector T cells can provide significant efficacy against solid tumors. Here, we highlight key learnings from the natural role of Vγ9Vδ2 T cells in the elimination of host cells bearing intracellular bacterial agents and we translate these into the setting of tumor therapy. We discuss the availability and relevance of preclinical models as well as currently available tools and knowledge from a drug development perspective. Finally, we compare advantages and disadvantages of existing therapeutic concepts and propose a role for Vγ9Vδ2 T cells in immune-oncology next to Cluster of Differentiation (CD) 3 activating therapies.

scholarly journals Early Pregnancy Human Decidua is Enriched with Activated, Fully Differentiated and Pro-Inflammatory Gamma/Delta T Cells with Diverse TCR Repertoires

2019 ◽  
Vol 20 (3) ◽  
pp. 687 ◽  
Author(s):  
Antonia Terzieva ◽  
Violeta Dimitrova ◽  
Lyubomir Djerov ◽  
Petya Dimitrova ◽  
Silvina Zapryanova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Pregnant Women ◽  
Early Pregnancy ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Maternal Immune System ◽  
Human Decidua ◽  
Maternal Fetal Interface

Pregnancy is a state where high and stage-dependent plasticity of the maternal immune system is necessary in order to equilibrate between immunosuppression of harmful responses towards the fetus and ability to fight infections. TCR γδ cells have been implicated in the responses in infectious diseases, in the regulation of immune responses, and in tissue homeostasis and repair. The variety of functions makes γδ T cells a particularly interesting population during pregnancy. In this study, we investigated the proportion, phenotype and TCR γ and δ repertoires of γδ T cells at the maternal–fetal interface and in the blood of pregnant women using FACS, immunohistochemistry and spectratyping. We found an enrichment of activated and terminally differentiated pro-inflammatory γδ T-cell effectors with specific location in the human decidua during early pregnancy, while no significant changes in their counterparts in the blood of pregnant women were observed. Our spectratyping data revealed polyclonal CDR3 repertoires of the δ1, δ2 and δ3 chains and γ2, γ3, γ4 and γ5 chains and oligoclonal and highly restricted CDR3γ9 repertoire of γδ T cells in the decidua and blood of pregnant women. Early pregnancy induces recruitment of differentiated pro-inflammatory γδ T-cell effectors with diverse TCR repertoires at the maternal–fetal interface.

Sustained Notch1 signaling instructs the earliest human intrathymic precursors to adopt a γδ T-cell fate in fetal thymus organ culture

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2444-2451 ◽  
Author(s):  
Marina García-Peydró ◽  
Virginia G. de Yébenes ◽  
María L. Toribio
Keyword(s):  
T Cells ◽  
T Cell ◽  
Organ Culture ◽  
Cell Fate ◽  
Γδ T Cells ◽  
Retroviral Vectors ◽  
Γδ T Cell ◽  
Fetal Thymus ◽  
Notch1 Signaling ◽  
The Impact

Abstract Notch1 activity is essential for the specification of T-lineage fate in hematopoietic progenitors. Once the T-cell lineage is specified, T-cell precursors in the thymus must choose between αβ and γδ lineages. However, the impact of Notch1 signaling on intrathymic pro-T cells has not been addressed directly. To approach this issue, we used retroviral vectors to express constitutively active Notch1 in human thymocyte progenitors positioned at successive developmental stages, and we followed their differentiation in fetal thymus organ culture (FTOC). Here we show that sustained Notch1 signaling impairs progression to the double-positive (DP) stage and efficiently diverts the earliest thymic progenitors from the main αβ T-cell pathway toward development of γδ T cells. The impact of Notch1 signaling on skewed γδ production decreases progressively along intrathymic maturation and is restricted to precursor stages upstream of the pre-T-cell receptor checkpoint. Close to and beyond that point, Notch1 is not further able to instruct γδ cell fate, but promotes an abnormal expansion of αβ-committed thymocytes. These results stress the stage-specific impact of Notch1 signaling in intrathymic differentiation and suggest that regulation of Notch1 activity at defined developmental windows is essential to control αβ versus γδ T-cell development and to avoid deregulated expansion of αβ-lineage cells. (Blood. 2003;102:2444-2451)

scholarly journals Human papillomavirus oncoproteins induce a reorganization of epithelial-associated γδ T cells promoting tumor formation

2017 ◽  
Vol 114 (43) ◽  
pp. E9056-E9065 ◽  
Author(s):  
Dorien Van hede ◽  
Barbara Polese ◽  
Chantal Humblet ◽  
Anneke Wilharm ◽  
Virginie Renoux ◽  
...  
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
T Cell ◽  
Γδ T Cells ◽  
Tumor Formation ◽  
T Cell Subsets ◽  
Γδ T Cell ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
The Impact

It has been shown that γδ T cells protect against the formation of squamous cell carcinoma (SCC) in several models. However, the role of γδ T cells in human papillomavirus (HPV)-associated uterine cervical SCC, the third-leading cause of death by cancer in women, is unknown. Here, we investigated the impact of γδ T cells in a transgenic mouse model of carcinogenesis induced by HPV16 oncoproteins. Surprisingly, γδ T cells promoted the development of HPV16 oncoprotein-induced lesions. HPV16 oncoproteins induced a decrease in epidermal Skint1 expression and the associated antitumor Vγ5+ γδ T cells, which were replaced by γδ T-cell subsets (mainly Vγ6+ γδlowCCR2+CCR6−) actively producing IL-17A. Consistent with a proangiogenic role, γδ T cells promoted the formation of blood vessels in the dermis underlying the HPV-induced lesions. In human cervical biopsies, IL-17A+ γδ T cells could only be observed at the cancer stage (SCC), where HPV oncoproteins are highly expressed, supporting the clinical relevance of our observations in mice. Overall, our results suggest that HPV16 oncoproteins induce a reorganization of the local epithelial-associated γδ T-cell subpopulations, thereby promoting angiogenesis and cancer development.

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