Generation of highly suppressive adaptive CD8+CD25+FOXP3+ regulatory T cells by continuous antigen stimulation

Abstract

Continuous antigen stimulation of CD4+CD25- T cells leads to generation of adaptive CD4+ CD25+ FOXP3+ regulatory T (TR) cells. Here, we show that highly suppressive adaptive CD8+ CD25+ FOXP3+ T cells can be generated in the same manner by continuous antigen stimulation in the presence of CD14+ monocytes. During the course of stimulation, acquisition of immunosuppressive properties develops in parallel with up-regulation and expression of cytotoxic molecules. The CD8+ TR cells inhibit CD4+ and CD8++ T cell proliferation and cytokine production, but do not alter the expression of granzyme A and granzyme B or perforin in CD8+ effector T cells. Although, the CD8+ TR cells express prostaglandin E2, IL-10 and TGF-β, the mechanism of suppression was independent of these soluble factors. In contrast to adaptive. CD4+ TR cells, the CD8+ TR cells suppress mainly by a contact-dependent mechanism as evident from transwell experiments. However, neither blocking antibodies to CTLA-4, CD80 nor CD86 could reverse CD8+ TR-mediated suppression, indicating that other mechanism(s) must be employed by these cells. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.