Anti-GARP Antibodies Inhibit Release of TGF-β by Regulatory T Cells via Different Modes of Action, but Do Not Influence Their Function In Vitro.
Journal
ImmunoHorizons
ISSN: 2573-7732
Titre abrégé: Immunohorizons
Pays: United States
ID NLM: 101708159
Informations de publication
Date de publication:
01 03 2023
01 03 2023
Historique:
received:
16
02
2023
accepted:
18
02
2023
entrez:
17
3
2023
pubmed:
18
3
2023
medline:
22
3
2023
Statut:
ppublish
Résumé
Regulatory T cells (Treg) play a critical role in controlling immune responses in diseases such as cancer or autoimmunity. Activated Treg express the membrane protein GARP (LRRC32) in complex with the latent form of the immunosuppressive cytokine TGF-β (L-TGF-β). In this study, we confirmed that active TGF-β was generated from its latent form in an integrin-dependent manner and induced TGF-β receptor signaling in activated human Treg. We studied a series of Abs targeting the L-TGF-β/GARP complex with distinct binding modes. We found that TGF-β receptor signaling could be inhibited by anti-TGF-β and by some, but not all, Abs against the L-TGF-β/GARP complex. Cryogenic electron microscopy structures of three L-TGF-β/GARP complex-targeting Abs revealed their distinct epitopes and allowed us to elucidate how they achieve blockade of TGF-β activation. Three different modes of action were identified, including a novel unusual mechanism of a GARP-binding Ab. However, blockade of GARP or TGF-β by Abs did not influence the suppressive activity of human Treg in vitro. We were also not able to confirm a prominent role of GARP in other functions of human Treg, such as FOXP3 induction and Treg stability. These data show that the GARP/TGF-β axis can be targeted pharmacologically in different ways, but further studies are necessary to understand its complexity and to unleash its therapeutic potential.
Identifiants
pubmed: 36928178
pii: 263533
doi: 10.4049/immunohorizons.2200072
pmc: PMC10563435
doi:
Substances chimiques
LRRC32 protein, human
0
Membrane Proteins
0
Receptors, Transforming Growth Factor beta
0
Transforming Growth Factor beta
0
Transforming Growth Factor beta1
0
Antibodies
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
200-212Informations de copyright
Copyright © 2023 The Authors.
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