Tolerogenic Semimature Dendritic Cells Induce Effector T-cell Hyporesponsiveness by the Activation of Antigen-Specific CD4+ CD25+ T-Regulatory Cells

Abstract

Objectives: Researchers recently discovered a group of semimature dendritic cells that induce autoimmune tolerance by activating host antigen-specific CD4+CD25+ T-regulatory cells. We hypothesized that donor semimature dendritic cells injected into recipients would induce effector T-cell hyporesponsiveness by activating CD4+CD25+ T-regulatory cells.

Materials and Methods: Donor myeloid semimature dendritic cells were cultivated for 6 days and were then stimulated with tumor necrosis factor α for 24 hours. BALB/c mice were pretreated with semimature dendritic cells to generate antigen-specific CD4+CD25+ T-regulatory cells in vivo. The role of CD4+CD25+ T-regulatory cells in transplant immunity was studied via mixed lymphocyte culture in vitro.

Results: Surface markers and cytokines secreted by semimature dendritic cells differed from those secreted by immature myeloid dendritic cells or mature dendritic cells. Semimature dendritic cells and immature myeloid dendritic cells did not activate allogenic lymphocyte responses in coculture studies. CD4+CD25+ T-regulatory cells of recipients challenged by donor semimature dendritic cells, which expressed a high level of interleukin-10, induced hyporesponsiveness in host effector T cells that were stimulated by donor splenocytes. In contrast, CD4+CD25+ T-regulatory cells did not induce hyporesponsiveness in effector T cells when the host T cells were stimulated by third-party antigen from DBA2 mice splenocytes.

Conclusions: Our findings confirm that semimature dendritic cells are an independent subgroup of dendritic cells in both immune function and morphologic profile. It may be the cytokine secretion profile of semimature dendritic cells (rather than that of surface markers) that has a key role in inducing CD4+CD25+ T-regulatory cells to express a high level of interleukin-10. Immunization with donor semimature dendritic cells may be an effective method of inducing transplant tolerance, but further evidence-based studies of that topic are necessary