Immunosurveillance by human γδ T lymphocytes: the emerging role of butyrophilins

Kabelitz, Dieter; Lettau, Marcus; Janßen, Ottmar

doi:10.12688/f1000research.11057.1

Cited by 22 publications

(13 citation statements)

References 94 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Specifically, exercise increases the proportions and absolute number of non-classical monocytes, which release higher levels of pro inflammatory cytokines (e.g., TNF-α and IL-18) that are essential for the activation and expansion of Vγ9Vδ2 T-cells (51). Moreover, the activation of Vγ9Vδ2 T-cells by ZOL and IPP requires expression of butyrophilin BTN3A molecules on monocytes (52), which could also be affected by exercise. Future studies should determine the role monocytes play in activating and expanding TCR-γδ T-cells after exercise.…”

Section: Discussionmentioning

confidence: 99%

Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells

et al. 2020

View full text Add to dashboard Cite

TCR-gamma delta (γδ) T-cells are considered important players in the graft-vs.-tumor effect following allogeneic hematopoietic cell transplantation (alloHCT) and have emerged as candidates for adoptive transfer immunotherapy in the treatment of both solid and hematological tumors. Systemic β-adrenergic receptor (β-AR) activation has been shown to mobilize TCR-γδ T-cells to the blood, potentially serving as an adjuvant for alloHCT and TCR-γδ T-cell therapy. We investigated if systemic β-AR activation, using acute dynamic exercise as an experimental model, can increase the mobilization, ex vivo expansion, and anti-tumor activity of TCR-γδ T-cells isolated from the blood of healthy humans. We also sought to investigate the β-AR subtypes involved, by administering a preferential β 1-AR antagonist (bisoprolol) and a non-preferential β 1 + β 2-AR antagonist (nadolol) prior to exercise as part of a randomized placebo controlled cross-over experiment. We found that exercise mobilized TCR-γδ cells to blood and augmented their ex vivo expansion by ∼182% compared to resting blood when stimulated with IL-2 and ZOL for 14-days. Exercise also increased the proportion of CD56+, NKG2D+/CD62L-, CD158a/b/e+ and NKG2A− cells among the expanded TCR-γδ cells, and increased their cytotoxic activity against several tumor target cells (K562, U266, 221.AEH) in vitro by 40-60%. Blocking NKG2D on TCR-γδ cells in vitro eliminated the augmented cytotoxic effects of exercise against U266 target cells. Furthermore, administering a β 1 + β 2-AR (nadolol), but not a β 1-AR (bisoprolol) antagonist prior to exercise abrogated the exercise-induced enhancement in TCR-γδ T-cell mobilization and ex vivo expansion. Furthermore, nadolol completely abrogated while bisoprolol partially inhibited the exercise-induced increase in the cytotoxic activity of the expanded TCR-γδ T-cells. We conclude that acute systemic β-AR activation in healthy donors markedly augments the mobilization, ex vivo expansion, and anti-tumor activity of Baker et al. Systemic β-AR Activation of Vγ9Vδ2 T-Cells TCR-γδ T-cells and that some of these effects are due to β 2-AR signaling and phenotypic shifts that promote a dominant activating signal via NKG2D. These findings highlight β-ARs as potential targets to favorably alter the composition of allogeneic peripheral blood stem cell grafts and improve the potency of TCR-γδ T-cell immune cell therapeutics.

show abstract

Section: Discussionmentioning

confidence: 99%

Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells

et al. 2020

View full text Add to dashboard Cite

show abstract

“…However, future applications will require a more in-depth understanding of their signaling mechanisms. Here, one new area of gd T cell research involves the role of butyrophilin in gd T cell activation (Kabelitz et al, 2017). In particular, it has been shown that butyrophilin 3A in antigen-presenting cells (APCs) is required for pAg recognition by Vg9Vd2 TCRs Hsiao et al, 2014;Palakodeti et al, 2012;Vavassori et al, 2013;Wang et al, 2013).…”

Section: Data Resourcesmentioning

confidence: 99%

A Structural Change in Butyrophilin upon Phosphoantigen Binding Underlies Phosphoantigen-Mediated Vγ9Vδ2 T Cell Activation

et al. 2019

View full text Add to dashboard Cite

Graphical Abstract Highlights d The crystal structure of HMBPP-bound intracellular BTN3A1 was determined at 1.97 Å d HMBPP forms hydrogen bonds with H 351 for efficient Vg9Vd2 T cell activation d An asymmetric intracellular dimer is involved in HMBPPmediated gd T cell activation d HMBPP doubles the binding force between extracellular BTN3A and Vg9Vd2 TCR SUMMARYHuman Vg9Vd2 T cells respond to microbial infections and malignancy by sensing diphosphate-containing metabolites called phosphoantigens, which bind to the intracellular domain of butyrophilin 3A1, triggering extracellular interactions with the Vg9Vd2 T cell receptor (TCR). Here, we examined the molecular basis of this ''inside-out'' triggering mechanism. Crystal structures of intracellular butyrophilin 3A proteins alone or in complex with the potent microbial phosphoantigen HMBPP or a synthetic analog revealed key features of phosphoantigens and butyrophilins required for gd T cell activation. Analyses with chemical probes and molecular dynamic simulations demonstrated that dimerized intracellular proteins cooperate in sensing HMBPP to enhance the efficiency of gd T cell activation. HMBPP binding to butyrophilin doubled the binding force between a gd T cell and a target cell during ''outside'' signaling, as measured by single-cell force microscopy. Our findings provide insight into the ''inside-out'' triggering of Vg9Vd2 T cell activation by phosphoantigen-bound butyrophilin, facilitating immunotherapeutic drug design.

show abstract

“…[65, 97] At steady-state, small intestinal γδ IEL RegIIIγ production requires commensal-induced epithelial MyD88 signaling,[65] again highlighting the crucial role of microbial recognition in IEL-mediated host defense. Although human γδ T cells respond directly to microbial products through TLR stimulation and the recognition of bacterial phosphoantigens (reviewed in [98]), whether γδ IELs are also capable of directly recognizing luminal microbes has yet to be determined.…”

Section: γδ Iels Prevent Acute Bacterial Translocation Across the Epimentioning

confidence: 99%

Sentinels at the Frontline: the Role of Intraepithelial Lymphocytes in Inflammatory Bowel Disease

Edelblum

2017

Curr Pharmacol Rep

View full text Add to dashboard Cite

Purpose of review Intestinal mucosal immunity is tightly regulated to ensure effective host defense against invasive microorganisms while limiting the potential for aberrant damage. In inflammatory bowel disease (IBD), an imbalance between effector and regulatory T cell populations results in an uncontrolled inflammatory response to commensal bacteria. Intraepithelial lymphocytes (IEL) are perfectly positioned within the intestinal epithelium to provide the first line of mucosal defense against luminal microbes or rapidly respond to epithelial injury. This review will highlight how IELs promote protective intestinal immunity and discuss the evidence indicating that altered IEL responses contribute to the pathogenesis of IBD. Recent findings Although the role of IELs in mucosal homeostasis has been largely underappreciated, many of the same factors that contribute to the dysregulation of host defense in IBD also adversely affect IELs. For example, IL-23 and the endoplasmic reticulum stress response can enhance IEL lytic activity toward enterocytes. Microbial dysbiosis or defective microbial recognition results in the loss of regulatory IELs, further amplifying these pro-inflammatory effects. Migration of T cells into or within the intraepithelial compartment has a profound effect on their differentiation or effector function demonstrating that IELs are exquisitely sensitive to changes in the local intestinal microenvironment. Summary Enhanced mechanistic insight into the regulation of IEL survival, differentiation and effector function may provide useful tools to modulate IEL surveillance or enhance IEL regulatory function. Elucidation of these processes may result in the development of novel therapeutics to reduce intestinal inflammation and reinforce the mucosal barrier in IBD.

show abstract

Immunosurveillance by human γδ T lymphocytes: the emerging role of butyrophilins

Cited by 22 publications

References 94 publications

Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells

Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells

A Structural Change in Butyrophilin upon Phosphoantigen Binding Underlies Phosphoantigen-Mediated Vγ9Vδ2 T Cell Activation

Sentinels at the Frontline: the Role of Intraepithelial Lymphocytes in Inflammatory Bowel Disease

Contact Info

Product

Resources

About