Diapedesis-Induced Integrin Signaling via LFA-1 Facilitates Tissue Immunity by Inducing Intrinsic Complement C3 Expression in Immune Cells.
Adult
Aged
Animals
Arthritis, Rheumatoid
/ immunology
Child
Child, Preschool
Complement C3
/ genetics
Female
Humans
Integrins
/ immunology
Lymphocyte Function-Associated Antigen-1
/ immunology
Lymphocytes
/ immunology
Male
Mice, Inbred C57BL
Middle Aged
Monocytes
/ immunology
Signal Transduction
/ immunology
Transendothelial and Transepithelial Migration
/ immunology
LAD-1
LFA-1
T cells
Th1 cells
autoimmunity
biomarker
complosome
integrins
intracellular complement
lymphocyte adhesion deficiency type 1
metabolism
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
17 03 2020
17 03 2020
Historique:
received:
04
03
2019
revised:
30
12
2019
accepted:
19
02
2020
entrez:
19
3
2020
pubmed:
19
3
2020
medline:
21
7
2020
Statut:
ppublish
Résumé
Intrinsic complement C3 activity is integral to human T helper type 1 (Th1) and cytotoxic T cell responses. Increased or decreased intracellular C3 results in autoimmunity and infections, respectively. The mechanisms regulating intracellular C3 expression remain undefined. We identified complement, including C3, as among the most significantly enriched biological pathway in tissue-occupying cells. We generated C3-reporter mice and confirmed that C3 expression was a defining feature of tissue-immune cells, including T cells and monocytes, occurred during transendothelial diapedesis, and depended on integrin lymphocyte-function-associated antigen 1 (LFA-1) signals. Immune cells from patients with leukocyte adhesion deficiency type 1 (LAD-1) had reduced C3 transcripts and diminished effector activities, which could be rescued proportionally by intracellular C3 provision. Conversely, increased C3 expression by T cells from arthritis patients correlated with disease severity. Our study defines integrins as key controllers of intracellular complement, demonstrates that perturbations in the LFA-1-C3-axis contribute to primary immunodeficiency, and identifies intracellular C3 as biomarker of severity in autoimmunity.
Identifiants
pubmed: 32187519
pii: S1074-7613(20)30077-7
doi: 10.1016/j.immuni.2020.02.006
pmc: PMC7111494
mid: NIHMS1569837
pii:
doi:
Substances chimiques
Complement C3
0
Integrins
0
Lymphocyte Function-Associated Antigen-1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
513-527.e8Subventions
Organisme : Medical Research Council
ID : MR/M004600/1
Pays : United Kingdom
Organisme : Intramural NIH HHS
ID : ZIA HL006223
Pays : United States
Organisme : NHLBI NIH HHS
ID : K22 HL125593
Pays : United States
Organisme : Wellcome Trust
ID : 102932/Z/13/Z
Pays : United Kingdom
Organisme : Intramural NIH HHS
ID : ZIA DK075149
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Intramural NIH HHS
ID : ZIA HL006222
Pays : United States
Organisme : Wellcome Trust
ID : 097261/Z/11/Z
Pays : United Kingdom
Organisme : Versus Arthritis
ID : 21226
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/J006742/1
Pays : United Kingdom
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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