Abstract
Regulatory T cell (Treg) therapy for immune modulation is a promising therapeutic strategy for the treatment and prevention of autoimmune disease and graft-versus-host disease (GvHD) after bone marrow transplantation. However, Treg are heterogeneous and express a variety of chemokine receptor molecules. The optimal subpopulation of Treg for therapeutic use may vary according to the pathological target. Indeed, clinical trials of Treg for the prevention of GvHD where the skin is a major target of the anti-host response have employed Treg derived from a variety of different sources. We postulated that for the effective treatment of GvHD-related skin pathology, Treg must be able to migrate to skin in order to regulate local alloimmune responses efficiently. To test the hypothesis that different populations of Treg display distinct efficacy in vivo based on their expression of tissue-specific homing molecules, we evaluated the activity of human Treg derived from two disparate sources in a model of human skin transplantation. Treg were derived from adult blood or cord blood and expanded in vitro. While Treg from both sources displayed similar in vitro suppressive efficacy, they exhibited marked differences in the expression of skin homing molecules. Importantly, only adult-derived Treg were able to prevent alloimmune-mediated human skin destruction in vivo, by virtue of their improved migration to skin. The presence of Treg within the skin was sufficient to prevent its alloimmune-mediated destruction. Additionally, Treg expressing the skin homing cutaneous lymphocyte antigen (CLA) were more efficient at preventing skin destruction than their CLA-deficient counterparts. Our findings highlight the importance of the careful selection of an effective subpopulation of Treg for clinical use according to the pathology of interest.
Highlights
Regulatory T cells (Treg) are a population of FOXP3expressing CD4+ T cells that play a central role in maintenance of self-tolerance and immune homeostasis
Treatment with Treg robustly extended the survival of human skin allografts in a dose-dependent manner (Figure 1A). 40 days after the adoptive transfer of cells, a significant number of intragraft human FOXP3+ cells together with increased intragraft FOXP3 gene expression was detected in human skin grafts from mice treated with Treg (Figures 1B and 1C)
BALB/c Rag22/2cc2/2 mice were transplanted with human skin and reconstituted with CD4+-depleted PBMC with or without an additional inoculation of Treg, and the skin-draining and contralateral axillary lymph nodes analysed by flow cytometry for the presence of human CD4+ cells
Summary
Regulatory T cells (Treg) are a population of FOXP3expressing CD4+ T cells that play a central role in maintenance of self-tolerance and immune homeostasis. To test the hypothesis that different populations of Treg display distinct efficacy in vivo based on their expression of tissue-specific homing molecules, we evaluated the activity of human Treg derived from two disparate sources in a model of human skin transplantation [16].
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