Enhanced selection of FoxP3+ T-regulatory cells protects CTLA-4-deficient mice from CNS autoimmune disease.

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.

• Authors: Johan Verhagen, Leona Gabrysová, Sophie Minaee, Catherine A Sabatos, Graham Anderson, Arlene H Sharpe, David C Wraith
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 9 Pg. 3306-11 (Mar 03 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19218450 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• CTLA-4 Antigen
• Ctla4 protein, mouse
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Interleukin-2 Receptor alpha Subunit

Topics

• Animals
• Antigens, CD (genetics, immunology, metabolism)
• CTLA-4 Antigen
• Disease Models, Animal
• Encephalomyelitis, Autoimmune, Experimental (immunology, metabolism)
• Female
• Forkhead Transcription Factors (immunology, metabolism)
• Gene Deletion
• Interleukin-2 Receptor alpha Subunit (immunology)
• Male
• Mice
• Mice, Knockout
• Spleen (immunology)
• Thymus Gland (immunology)