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T Cell Activation and Clonal Selection01:22

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T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...
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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
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γ9δ2 T cells detect mevalonate diphosphate via BTN3A3.

Yiming Jin1, Khiem Nguyen1, Girija Pawge1

  • 1Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269, USA.

Cellular and Molecular Life Sciences : CMLS
|November 14, 2025
PubMed
Summary

Mevalonate diphosphate (MPP) activates γ9δ2 T cells and binds to Butyrophilin-3A3 (BTN3A3), revealing MPP as a natural ligand for BTN3A3 and expanding understanding of BTN immune sensing pathways.

Keywords:
B30.2-SPRY domainCancer immunotherapyImmunologyIsoprenoid biosynthesisMolecular glueT cell receptor

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Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Butyrophilins (BTNs) are key sensors of phosphoantigens (pAgs) involved in immune responses.
  • BTN3A1 recognizes exogenous HMBPP and endogenous DMAPP/IPP, activating γ9δ2 T cells.
  • The function and ligands of the related BTN3A3 remain largely unknown.

Purpose of the Study:

  • To investigate the potential ligands and functions of Butyrophilin-3A3 (BTN3A3).
  • To explore the role of Mevalonate diphosphate (MPP) in γ9δ2 T cell activation.
  • To elucidate the interaction between BTN3A3, MPP, and immune cell activation.

Main Methods:

  • Computational docking to assess ligand binding affinity to BTN3A1 and BTN3A3.
  • Functional assays measuring γ9δ2 T cell activation by various compounds.
  • 31P NMR and LC-MS to confirm molecular interactions and metabolic changes.
  • Cell-based co-culture experiments with transfected cells.

Main Results:

  • Mevalonate diphosphate (MPP) exhibited high docking scores with both BTN3A1 and BTN3A3.
  • MPP activated γ9δ2 T cells, confirming it as a functional ligand.
  • 31P NMR confirmed MPP binding to BTN3A1 and BTN3A3 internal domains.
  • 6-Fluoromevalonate (6-FM), an MPP-related compound, also activated γ9δ2 T cells.
  • Transfected cells expressing BTN2A1 with BTN3A1 or BTN3A3 responded to 6-FM.

Conclusions:

  • Mevalonate diphosphate (MPP) is identified as a natural ligand for Butyrophilin-3A3 (BTN3A3).
  • This finding expands the known repertoire of phosphoantigen sensors and their ligands.
  • The study provides a foundation for understanding BTN3A3's biological roles in immunity.