CTLA‐4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in mice

• Published in: Arthritis and rheumatism Vol. 60; no. 1; pp. 123 - 132
• Main Authors: Kolar, Paula, Knieke, Karin, Hegel, J. Kolja E., Quandt, Dagmar, Burmester, Gerd‐R., Hoff, Holger, Brunner‐Weinzierl, Monika C.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.01.2009; Wiley
• Subjects: Adoptive Transfer; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Biological and medical sciences; CD4 Antigens - metabolism; Cell Death - immunology; Cell Division - immunology; Cell Survival - immunology; Cells, Cultured; CTLA-4 Antigen; Diseases of the osteoarticular system; Flow Cytometry; Forkhead Transcription Factors - metabolism; Homeostasis - immunology; Interleukin-2 Receptor alpha Subunit - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Signal Transduction - immunology; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - metabolism; Vertebrata; Mammalia; Mouse; Immunological investigation; Animal; Rodentia; T-Lymphocyte; Rheumatology; Homeostasis
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.24181

Objective CD4+CD25+ regulatory T cells (known as Treg cells) suppress unwanted and autoreactive T cell responses. Treg cells express the costimulatory molecule CTLA‐4 intracellularly, but the mechanisms by which Treg cells exploit CTLA‐4 signaling remain unclear. The present study was undertaken to investigate the role of CTLA‐4 in controlling the homeostasis and suppressive function of Treg cells. Methods Murine Treg cells were analyzed by flow cytometry for coexpression of CTLA‐4 and typical Treg cell–expressed molecules, and the influence of CTLA‐4 on T cell proliferation, suppression, and apoptosis was investigated by in vitro assays. To analyze the importance of CTLA‐4 in Treg cell–mediated suppression in vivo, wild‐type Treg cells were transferred into CTLA‐4–deficient mice displaying lymphoproliferation, and survival was monitored over time. Results A strong correlation between expression of forkhead box P3 and ex vivo expression of CTLA‐4 in Treg cells was observed. Inhibition of CTLA‐4 signaling in Treg cells during in vitro stimulation increased cell cycling and led to enhanced activation‐induced cell death (AICD), which was mediated by CD95/CD95 ligand–induced activation of caspases. Blockade of CTLA‐4 signaling resulted in impairment of the suppressive capacity of Treg cells. Despite these effects, high amounts of Treg cells persisted in CTLA‐4–deficient mice. Results of transfer experiments in CTLA‐4–deficient mice showed that the mice had a significantly prolonged lifespan when CTLA‐4–competent Treg cells were injected. Conclusion Expression of CTLA‐4 on Treg cells serves to control T cell proliferation, to confer resistance against AICD, and to maintain the suppressive function of Treg cells.