Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation.
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
18
06
2021
accepted:
15
07
2022
pubmed:
24
8
2022
medline:
20
9
2022
entrez:
23
8
2022
Statut:
ppublish
Résumé
CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both receptors share the same ligands, CD80 and CD86, the specific requirement for two distinct ligands remains obscure. In the present study, we demonstrate that, although CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, this process results in separate fates for CTLA-4 itself. In the presence of CD80, CTLA-4 remained ligand bound, and was ubiquitylated and trafficked via late endosomes and lysosomes. In contrast, in the presence of CD86, CTLA-4 detached in a pH-dependent manner and recycled back to the cell surface to permit further transendocytosis. Furthermore, we identified clinically relevant mutations that cause autoimmune disease, which selectively disrupted CD86 transendocytosis, by affecting either CTLA-4 recycling or CD86 binding. These observations provide a rationale for two distinct ligands and show that defects in CTLA-4-mediated transendocytosis of CD86 are associated with autoimmunity.
Identifiants
pubmed: 35999394
doi: 10.1038/s41590-022-01289-w
pii: 10.1038/s41590-022-01289-w
pmc: PMC9477731
doi:
Substances chimiques
Antigens, CD
0
Antigens, Differentiation
0
B7-1 Antigen
0
B7-2 Antigen
0
CD28 Antigens
0
CTLA-4 Antigen
0
Cell Adhesion Molecules
0
Ligands
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1365-1378Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/H013598/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 204798
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/H013598/2
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/H013598
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00008/4
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M009203/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 207547/Z/17/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 110297/Z/15/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 102186/B/13/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 204798/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N001435/1
Pays : United Kingdom
Organisme : Versus Arthritis
ID : 21147
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022. The Author(s).
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