High sensitivity of host Helios+/Neuropilin-1+ Treg to pretransplant conditioning hampers development of OX40bright/integrin-β7+ regulatory cells in acute gastrointestinal GvHD

Nikolett Lupsa; Barbara Érsek; Csenge Böröczky; Dávid Kis; Eszter Szarka; Katalin Lumniczky; Géza Sáfrány; Zoltán S Zádori; Árpád Szöőr; Edit I Buzás; Zoltán Pós

doi:10.1002/eji.202350619

High sensitivity of host Helios⁺/Neuropilin-1⁺ Treg to pretransplant conditioning hampers development of OX40^bright/integrin-β7⁺ regulatory cells in acute gastrointestinal GvHD

Eur J Immunol. 2024 Mar 26:e2350619. doi: 10.1002/eji.202350619. Online ahead of print.

Authors

Affiliations

¹ Department of Genetics, Cell and Immunobiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
² Unit of Radiation Medicine, Department of Radiobiology and Radiohygiene, National Public Health Center, Budapest, Hungary.
³ Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
⁴ Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
⁵ Immunproteogenomics Extracellular Vesicle Research Group of the Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary.
⁶ Extracellular Vesicle Research Group, Hungarian Center of Excellence Molecular Medicine, Budapest, Hungary.

PMID: 38532599
DOI: 10.1002/eji.202350619

Abstract

This study sought to compare the behavior of Treg subsets displaying different coexpression patterns of Neuropilin-1 (Nrp1) and Helios, under the influence of gut stress unrelated to hematopoietic stem cell transplantation, pretransplantation conditioning, and posttransplant gastrointestinal acute graft versus host disease (GI-aGvHD). Host CD4⁺/CD25^hi/Foxp3⁺ Treg cells, identified by flow cytometry, were isolated from various tissues of mice affected by these stressors. Expression of CD25, CTLA-4, CD39, OX40, integrin-β7, LAG3, TGFβ/LAP, granzyme-A, -B, and interleukin-10 was compared in four Treg subsets displaying Helios or Nrp1 only, both or none. Fluorescence-activated cell sorter-sorted Treg subsets, displaying markers affected in a conditioning- and GI-aGVHD-restricted manner, were further investigated by transcriptome profiling and T-cell suppression assays. We found that conditioning by irradiation greatly diminished the relative frequency of Helios⁺/Nrp1⁺ Treg, shifting the balance toward Helios^-/Nrp1^- Treg in the host. Upregulation of integrin-β7 and OX40 occurred in GI-aGvHD-dependent manner in Helios⁺/Nrp1⁺ cells but not in Helios^-/Nrp1^- Treg. Sorted Treg subsets, confirmed to overexpress Nrp1, Helios, OX40, or integrin-β7, displayed superior immunosuppressive activity and enrichment in activation-related messenger RNA transcripts. Our data suggest that conditioning-induced shrinkage of the Nrp1⁺/Helios⁺ Treg subset may contribute to the development of GI-GvHD by impairing gut homing and decreasing the efficiency of Treg-mediated immunosuppression.

Keywords: Acute graft versus host disease; CD304; Helios; Neuropilin‐1; Treg.

Abstract

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