Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives

Autor: Margarida Lima, C. Ponte, C Vasconcelos, Alexandrina Martins, R. Campanilho-Marques, António Marinho, Berta Martins, Constantin Fesel, A. M. Figueiredo, Oriana Marques, C. Carvalho, João Viana, Neuza Maria Brunoro Costa, T. Cóias, Maria Francisca Moraes-Fontes, S. I. Godinho, Bárbara Leal, A. Gomes da Costa
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Interleukin 2
Adult
Male
Regulatory T cell
Immunology
Population
Recent Thymic Emigrant
chemical and pharmacologic phenomena
Autoimmunity
Lymphocyte Activation
T-Lymphocytes
Regulatory
regulatory T cells
03 medical and health sciences
Young Adult
Downregulation and upregulation
systemic lupus erythematosus
medicine
Immunology and Allergy
Humans
Lupus Erythematosus
Systemic
Family
IL-2 receptor
education
Aged
education.field_of_study
business.industry
Translational
Interleukin-2 Receptor alpha Subunit
FOXP3
hemic and immune systems
Original Articles
Middle Aged
HCC MED
Flow Cytometry
cytokines
Up-Regulation
030104 developmental biology
medicine.anatomical_structure
Phenotype
Interleukin-2
Leukocyte Common Antigens
Original Article
Female
business
Alpha chain
medicine.drug
Zdroj: Clinical and Experimental Immunology
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Agência para a Sociedade do Conhecimento (UMIC)-FCT-Sociedade da Informação
instacron:RCAAP
ISSN: 1365-2249
0009-9104
Popis: Summary Forkhead box P3 (FoxP3)+ regulatory T cells (Tregs) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)-2 receptor alpha chain]. Low-dose IL-2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE Treg phenotype, we studied its role through developmentally defined regulatory T cell (Treg) subsets in 45 SLE patients, 103 SLE-unaffected first-degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25-encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to Treg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4+FoxP3+CD45RO–CD31+ recent thymic emigrant Tregs. This first component effect influenced the proportions of circulating CD4+FoxP3highCD45RO+ activated Tregs. (2) In contrast, patients and unaffected relatives differed sharply in their activated Treg CD25 state: while relatives as control subjects up-regulated CD25 strongly in these cells during differentiation from naive Tregs, SLE patients specifically failed to do so. This CD25 up-regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated Tregs, but not to their circulating numbers. Both effects were found related to T cell IL-2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early Tregs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up-regulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg-directed therapies can be monitored more effectively when taking this distinction into account.
Databáze: OpenAIRE
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