Induction of FOXP3‐expressing regulatory CD4^pos T cells by human mature autologous dendritic cells

Abstract

Current literature suggests that T cells recognizing antigen on mature dendritic cells (DC) differentiate into effector T cells whereas tolerance is induced when antigen is presented by immature DC. We investigated the consequences of the interactions between immature or lipopolysaccharide-matured DC and CD4 pos T lymphocytes in absence of foreign antigen. While immature DC did not induce significant CD4 pos T cell activation, we observed that a significant fraction of CD4 pos T cells cultured with mature autologous DC displayed phenotypic features of activation and produced IL-2, IFN-+ , IL-10 and TGF-g . Furthermore, CD4 pos T lymphocytes primed by mature, but not immature, autologous DC acquired regulatory properties. Indeed, when added to an allogeneic mixed leukocyte reaction, they suppressed the response of alloreactive T lymphocytes to the priming DC while responses to third-party stimulators were spared. The generation of CD4 pos T cells with regulatory function by autologous stimulation did not require the presence of natural CD4 pos CD25 pos regulatory T cells. In addition, the acquisition of regulatory function by CD4 pos CD25 neg T cells stimulated by autologous mature DC was accompanied by the induction of FOXP3 expression. Our data suggest that during inflammatory conditions, presentation of self antigens by mature DC to autologous T lymphocytes could contribute to the generation of regulatory mechanisms.

Antigen‐induced, tolerogenic CD11c+,CD11b+ dendritic cells are abundant in Peyer's patches during the induction of oral tolerance to type II collagen and suppress experimental collagen‐induced arthritis

“…In addition, the release of IL-10 by CD11cϩ,CD11bϩ DCs from Peyer's patches of tolerized mice could play a role in inducing CD4ϩ, CD25ϩ T regulatory cells to differentiate. Several welldesigned studies have demonstrated that immature DCs, semi-immature DCs, fully mature DCs, or granulocytemacrophage colony-stimulating factor-pulsed DCs could cause naive T cells to differentiate into CD4ϩ,CD25ϩ T regulatory cells in the periphery (35)(36)(37)(38). However, the specialized subset of tolerogenic DCs generated under physiologic conditions, such as those seen in the nontransgenic autoimmune arthritis animal model, is yet to be identified.…”

Preclinical full-scale evaluation of dendritic cells transfected with autologous tumor-mRNA for melanoma vaccination

“…In the in vivo vaccine setting, T cells stimulated by mockDCs could in any case exert an important regulatory influence on the vaccine response, as has been assumed with regard to AMLR in conventional inflammatory conditions. [22][23][24] The DC vaccine could also result in expansion of autoreactive T cells recognizing transfected antigens. Accordingly, patients should be monitored carefully with respect to potential autoimmune side effects.…”

The role of dendritic cells and regulatory T cells in the regulation of allergic asthma

“…Naturally occurring Treg cells were traditionally described to be thymically-derived with the function of maintaining systemic homeostasis to control total lymphocyte numbers in order to protect the integrity of tissues and organs in vivo (Sakaguchi et al, 2001). More recently, Treg populations have been induced in vitro and in vivo via culturing with cytokines or in mouse models via pathogenic or allergenic stimulation (Verhasselt et al, 2004;Kretschmer et al, 2005;Luo et al, 2005;Skapenko et al, 2005;Moo-Young et al, 2006;Nicolson & Wraith, 2006;Strickland et al, 2006). The induced Treg populations also have the ability to control other lymphocytes in vivo however they differ from naturally occurring Treg in a number of ways which will be discussed below.…”

“…In this context, an evolving role for RTDC may be to promote Treg cells capable of directly and actively suppressing the immune response to antigen once the antigen has been cleared (Jonuleit et al, 2001;Weiner, 2001;Martin et al, 2003;Verhasselt et al, 2004;Chen, 2006;Tarbell et al, 2006;Cools et al, 2007;Fujita et al, 2008). Akbari et al (2001) demonstrated that respiratory exposure to antigen (OVA) could induce phenotypically mature pulmonary DC that transiently produced IL-10.…”