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.

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.

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Shimon Sakaguchi
Department of Experimental Pathology, Institute for Medical Sciences, Kyoto University
(Laboratory of Experimental Immunology, IFReC, Osaka University)
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