Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production

• Published in: Blood Vol. 108; no. 1; pp. 390 - 399
• Main Authors: Zeiser, Robert, Nguyen, Vu H., Beilhack, Andreas, Buess, Martin, Schulz, Stephan, Baker, Jeanette, Contag, Christopher H., Negrin, Robert S.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01-07-2006; The Americain Society of Hematology; The American Society of Hematology
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Bone marrow, stem cells transplantation. Graft versus host reaction; Calcineurin - pharmacology; Calcineurin - physiology; CD4 Antigens - biosynthesis; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Interleukin-2 - biosynthesis; Interleukin-2 Receptor alpha Subunit - biosynthesis; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Mutant Strains; Species Specificity; Structure-Activity Relationship; Survival Rate; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Human; Graft versus leukemia reaction; Immunopathology; Immune response; Calcineurin; Stem cell; Leukemia; Cytokine; Hematopoietic cell; Homograft; Graft versus host reaction; Malignant hemopathy; Interleukin 2; T-Lymphocyte; Graft; Immunosuppressive agent; Regulatory cell
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-01-0329

CD4+CD25+ regulatory T (Treg) cells control immunologic tolerance and antitumor immune responses. Therefore, in vivo modification of Treg function by immunosuppressant drugs has broad implications for transplantation biology, autoimmunity, and vaccination strategies. In vivo bioluminescence imaging demonstrated reduced early proliferation of donor-derived luciferase-labeled conventional T cells in animals treated with Treg cells after major histocompatibility complex mismatch bone marrow transplantation. Combining Treg cells with cyclosporine A (CSA), but not rapamycin (RAPA) or mycophenolate mofetil (MMF), suppressed Treg function assessed by increased T-cell proliferation, graft-versus-host disease (GVHD) severity, and reduced survival. Expansion of Treg and FoxP3 expression within this population was lowest in conjunction with CSA, suggesting that calcineurin-dependent interleukin 2 (IL-2) production is critically required for Treg cells in vivo. The functional defect of Treg cells after CSA exposure could be reversed by exogenous IL-2. Further, the Treg plus RAPA combination preserved graft-versus-tumor (GVT) effector function against leukemia cells. Our data indicate that RAPA and MMF rather than CSA preserve function of Treg cells in pathologic immune responses such as GVHD without weakening the GVT effect. (Blood. 2006;108:390-399)