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Selectins01:25

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Cell adhesion is  an essential aspect of multicellularity. While stable cell interactions usually occur between cells of the same type, transient cell interactions occur between cells of different tissue types, such as between neutrophils and endothelial cells. Selectins are one class of cell adhesion molecules (CAMs) that bind carbohydrate ligands to form transient cell adhesion. They are rod-like proteins with a long extracellular part of variable length ending with the lectin domain,...
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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
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Optimizing human Treg immunotherapy by Treg subset selection and E-selectin ligand expression.

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Naïve Tregs (nvTreg) show promise for immunotherapy but have poor homing. Glycan engineering enhanced their ability to target inflammation and suppress Graft-versus-Host Disease, making them ideal for cell therapy.

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Area of Science:

  • Immunology
  • Cell Therapy
  • Glycobiology

Background:

  • Human regulatory T cells (Tregs) are promising for immunotherapy but show biological variability.
  • Challenges exist in utilizing Tregs clinically due to their plasticity and functional heterogeneity.

Purpose of the Study:

  • To investigate the clinical relevance of defined human Treg subsets.
  • To assess the impact of in vitro expansion and glycan engineering on Treg function and homing.

Main Methods:

  • Analysis of freshly isolated and expanded human peripheral blood mononuclear cell (PBMC)-derived Tregs.
  • Assessment of Treg proliferation, suppressive capacity, and lineage fidelity.
  • Evaluation of sLeX expression and Fucosyltransferase VII activity.
  • Ex vivo glycan engineering (exofucosylation) of Tregs.
  • Inhibition assays for xenogeneic Graft-versus-Host Disease (aGVHD).

Main Results:

  • Naïve Tregs (nvTregs) demonstrated superior proliferation, stimulated suppressive capacity, and Treg lineage fidelity compared to memory Tregs (memTregs).
  • nvTregs exhibited low sLeX expression and poor homing capacity due to low Fucosyltransferase VII activity.
  • In vitro expansion enhanced nvTreg suppressive function but did not alter their glycome.
  • Exofucosylation significantly increased nvTreg sLeX expression, promoting endothelial adhesion and enhancing aGVHD inhibition.

Conclusions:

  • The immature Treg glycome is uniquely regulated.
  • Adult PBMCs are a viable source for autologous therapeutic Tregs.
  • Subset selection and glycan engineering are crucial for optimizing Treg immunomodulation and tropism for inflammatory sites in cell therapy.