CTLA-4 Control over Foxp3 + Regulatory T Cell Function

• DOI: 10.1126/science.1160062
• Publication Date: 2008-10-10T18:04:20Z
• Authors: Kajsa Wing; Yasushi Onishi; Paz Prieto-Martin; Tomoyuki Yamaguchi; Makoto Miyara; Zoltan Fehervari; Takashi Nomura; Shimon Sakaguchi
• Keywords: Male; Leukemia; Antigen-Presenting Cells; Down-Regulation; Autoimmunity; Forkhead Transcription Factors; Dendritic Cells; CD8-Positive T-Lymphocytes; Immunoglobulin E; Lymphocyte Activation; Autoimmune Diseases; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Antigens, CD; Immunoglobulin G; B7-1 Antigen; Immune Tolerance; Animals; CTLA-4 Antigen; Female; B7-2 Antigen; Lymphocytes

Naturally occurring Foxp3 + CD4 + regulatory T cells (Tregs) are essential for maintaining immunological self-tolerance and immune homeostasis. Here, we show that a specific deficiency of cytotoxic T lymphocyte antigen 4 (CTLA-4) in Tregs results in spontaneous development of systemic lymphoproliferation, fatal T cell–mediated autoimmune disease, and hyperproduction of immunoglobulin E in mice, and it also produces potent tumor immunity. Treg-specific CTLA-4 deficiency impairs in vivo and in vitro suppressive function of Tregs—in particular, Treg-mediated down-regulation of CD80 and CD86 expression on dendritic cells. Thus, natural Tregs may critically require CTLA-4 to suppress immune responses by affecting the potency of antigen-presenting cells to activate other T cells.