Abstract
BackgroundType 1 regulatory T (Tr1) cells, characterized by the secretion of high levels of the anti-inflammatory cytokine interleukin-10 (IL-10), play an important role in the regulation of autoimmune diseases and transplantation. However, effective strategies that specifically induce Tr1 cells in vivo are limited. Furthermore, the pathways controlling the induction of these cells in vivo are not well understood.Methodology/Principal FindingsHere we report that nasal administration of anti-CD3 antibody induces suppressive Tr1 cells in mice. The in vivo induction of Tr1 cells by nasal anti-CD3 is dependent on IL-27 produced by upper airway resident dendritic cells (DCs), and is controlled by the transcription factors aryl hydrocarbon receptor (AHR) and c-Maf. Subsequently, IL-21 acts in an autocrine fashion to expand and maintain the Tr1 cells induced in vivo by nasally administered anti-CD3.Conclusions/SignificanceOur findings identify a unique approach to generate Tr1 cells in vivo and provide insights into the mechanisms by which these cells are induced.
Highlights
The generation of functional regulatory T cells in vivo is a major goal for the treatment of immune-mediated diseases
Upon activation with anti-CD3 in vitro, FACS sorted CD4+CD25GFP(IL-10)+ T cells secreted IL-10 and IFN-c (Figure 1B). This cytokine pattern is consistent with a Tr1 cell phenotype [10], and was not seen when CD4+CD25-green fluorescent reporter (GFP)(IL-10)- naive T cells or CD4+CD25+GFP(IL-10)- T cells were sorted from anti-CD3 treated mice and activated in vitro (Figure 1B)
We have previously shown that the suppressive T cells induced by the oral administration of anti-CD3 are characterized by the expression of membrane-bound transforming growth factor-beta (TGF-b) (LAP)
Summary
The generation of functional regulatory T cells in vivo is a major goal for the treatment of immune-mediated diseases. Tr1 cells do not constitutively express the transcription factor forkhead box p3 (Foxp3), which is a lineage specific marker for both naturally occurring and induced CD4+CD25+ regulatory T cells [2]. Upon TCR stimulation, Tr1 cells can mediate bystander suppression by the local release of IL-10 and TGF-b that act on both antigen presenting cells (APCs) and T cells to suppress co-stimulatory molecule expression and proinflammatory cytokine production, respectively [5]. Type 1 regulatory T (Tr1) cells, characterized by the secretion of high levels of the anti-inflammatory cytokine interleukin-10 (IL-10), play an important role in the regulation of autoimmune diseases and transplantation. The pathways controlling the induction of these cells in vivo are not well understood
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