Adenosine 2a Receptor Signal Blockade of Murine Autoimmune Arthritis via Inhibition of Pathogenic Germinal Center-Follicular Helper T Cells.
Adenosine
/ analogs & derivatives
Adenosine A2 Receptor Agonists
Adoptive Transfer
Animals
Arthritis, Experimental
/ immunology
Autoantigens
Autoimmune Diseases
CD4-Positive T-Lymphocytes
Cytokines
/ immunology
Disease Models, Animal
Germinal Center
Glucose-6-Phosphate Isomerase
/ immunology
Mice
Mice, Knockout
Mice, Transgenic
Phenethylamines
/ pharmacology
Receptor, Adenosine A2A
/ genetics
Receptors, Antigen, T-Cell, alpha-beta
/ genetics
Signal Transduction
T-Lymphocytes, Helper-Inducer
/ drug effects
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
26
04
2018
accepted:
29
11
2018
pubmed:
6
12
2018
medline:
3
1
2020
entrez:
6
12
2018
Statut:
ppublish
Résumé
CD4 germinal center (GC)-follicular helper T (Tfh) cells are important in the pathogenesis of autoimmune arthritis. Previous studies have shown that adenosine 2a receptor (A2aR; Adora2a) signaling can divert CD4 T cells away from the GC-Tfh cell lineage during the primary response to foreign antigens. This study was undertaken to examine the effects of A2aR signaling on CD4 T cells during the recognition of self antigen in a murine model of autoimmune arthritis. Wild-type and Adora2a-deficient mouse KRN T cell receptor-transgenic CD4 T cells specific for glucose-6-phosphate isomerase (GPI)/I-A CGS treatment inhibited the development of arthritis and differentiation of KRN GC-Tfh cells, blocked the appearance of high-affinity GPI-specific and IgG1 isotype class-switched polyclonal plasmablasts, and led to a reduction in serum titers of anti-GPI IgG1. In addition, therapeutic administration of CGS after the onset of arthritis blocked further disease progression in association with reductions in the number of KRN GC-Tfh cells and anti-GPI IgG1 serum titers. Strong A2aR signaling diverts autoreactive CD4 T cell differentiation away from the GC-Tfh cell lineage, thus reducing help for the differentiation of dangerous autoreactive B cells that promote arthritis. These data in a mouse model of autoimmune arthritis suggest that A2aR and its downstream signaling pathways in CD4 T cells may be promising therapeutic targets for interfering with potentially dangerous autoreactive GC-Tfh cell differentiation.
Identifiants
pubmed: 30516351
doi: 10.1002/art.40796
pmc: PMC6483839
mid: NIHMS1000748
doi:
Substances chimiques
Adenosine A2 Receptor Agonists
0
Adora2a protein, mouse
0
Autoantigens
0
Cytokines
0
Phenethylamines
0
Receptor, Adenosine A2A
0
Receptors, Antigen, T-Cell, alpha-beta
0
2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
120225-54-9
Glucose-6-Phosphate Isomerase
EC 5.3.1.9
Gpi1 protein, mouse
EC 5.3.1.9
Adenosine
K72T3FS567
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
773-783Subventions
Organisme : NIAID NIH HHS
ID : T32 AI007313
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA077598
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI035296
Pays : United States
Organisme : Lupus Link Minnesota
Pays : International
Informations de copyright
© 2018, American College of Rheumatology.
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