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Enhanced selection of FoxP3+ T-regulatory cells protects CTLA-4-deficient mice from CNS autoimmune disease.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2009 Mar 03; Vol. 106 (9), pp. 3306-11. Date of Electronic Publication: 2009 Feb 13. - Publication Year :
- 2009
-
Abstract
- It is generally acknowledged that cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4/CD152) plays a pivotal role in the regulation of T-cell activation and the establishment of self-tolerance in the periphery. CTLA-4-deficient (CTLA-4KO) mice develop a lymphoproliferative disorder and die within 4 weeks of birth, suggesting a role for CTLA-4 in T-cell homeostasis or the development and activity of T-regulatory (Treg) cells. To study the role of CTLA-4 in the control of experimental autoimmune encephalomyelitis (EAE), we have generated a CTLA-4KO mouse in which >90% of all CD4(+) T cells bear a Vbeta8.2 transgenic T-cell receptor that is specific for myelin basic protein peptide Ac1-9 (ASQKRPSQR). These mice do not develop spontaneous lymphoproliferative disease or EAE and are resistant to disease induction. This correlates with a higher frequency of functional FoxP3(+) Treg cells in the spleen and thymus of CTLA-4KO mice. The absence of CTLA-4-mediated suppression of CD28 signaling resulted in the early expression of FoxP3 on double-positive cells in the thymic cortex. We conclude that CTLA-4 is not essential for the peripheral function of FoxP3(+) Treg cells but plays a pivotal role in their thymic selection.
- Subjects :
- Animals
Antigens, CD genetics
CTLA-4 Antigen
Disease Models, Animal
Female
Gene Deletion
Interleukin-2 Receptor alpha Subunit immunology
Male
Mice
Mice, Knockout
Spleen immunology
Thymus Gland immunology
Antigens, CD immunology
Antigens, CD metabolism
Encephalomyelitis, Autoimmune, Experimental immunology
Encephalomyelitis, Autoimmune, Experimental metabolism
Forkhead Transcription Factors immunology
Forkhead Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 106
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 19218450
- Full Text :
- https://doi.org/10.1073/pnas.0803186106