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CTLA-4 Control over Foxp3+ Regulatory T Cell Function. (Prof. Sakaguchi in Science)

Naturally occurring Foxp3+CD4+ regulatory T cells (Tregs) are essential for maintaining immunological self-tolerance and immune homeostasis. Here, the authors 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 (Figure A).

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.

322_271_F3A.jpg Figure A: Treg-specific CTLA-4 deficiency promotes tumor immunity.
BALB/c nu/nu mice received 3 x 107 splenocytes from FIC or CKO mice, followed by intradermal inoculation of 1.5 x 105 RLmale1 leukemia cells. Crosses indicate death due to tumor growth. (B) BALB/cCD25- cells (1.5 x 107) were cotransferred with 3.8 x 105 CD25highCD4+ T cells from CKO or FIC mice and inoculated with 1.5 x 105 RLmale1 cells (n=3). Tumor diameters were measured every other day for 6 weeks. Mice were euthanized when tumor diameters exceeded 20 mm.


Review for this Article


Shimon Sakaguchi
Department of Experimental Pathology, Institute for Medical Sciences, Kyoto University
(Laboratory of Experimental Immunology, IFReC, Osaka University)
53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
Tel: +81-75-751-3851 Fax: +81-75-751-3820