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Title: Antigen-specific CD4+ CD25+ T cells induced by locally expressed ICOS-Ig: The role of Foxp3, Perforin, Granzyme B and IL-10.
Austin Authors: Christiansen, Dale;Mouhtouris, Effie ;Hodgson, Russell;Sutton, Vivien R;Trapani, Joseph A;Ierino, Francesco L;Sandrin, Mauro S 
Affiliation: Department of Surgery, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Nephrology, Austin Health, Heidelberg, Victoria, Australia
Cancer Cell Death/Killer Cell Biology Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
Issue Date: Nov-2019
Date: 2019-06-21
Publication information: Transplant international : official journal of the European Society for Organ Transplantation 2019; 32(11): 1203-1215
Abstract: We have previously reported that ICOS-Ig expressed locally by a graft induces a perigraft cellular accumulation of CD4+ CD25+ Foxp3+ T cells and specific xenograft prolongation. In the present study we isolated and purified CD4+ CD25+ T cells from ICOS-Ig secreting grafts to examine their phenotype, and used knockout and mutant mice to examine molecules involved in graft prolongation. The mechanism of xenograft survival observed with ICOS-Ig-secreting PIEC grafts was examined using selected knockout mice. CD4+ CD25+ T cells were isolated from xenografts secreting ICOS-Ig for phenotyping by flow cytometry, gene expression analysis by real-time PCR and regulatory function by suppression of xenogeneic or allogeneic primed CD4 T cells in vivo. Graft prolongation is dependent on a pre-existing Foxp3+ Treg, IL-10, perforin and granzyme B. CD4+ CD25+ Foxp3+ T cells isolated from xenografts secreting ICOS-Ig have a phenotype consistent with nTreg but with a higher expression of CD275 (ICOSL), expression of CD278 (ICOS) and MHC II and loss of CD73. Moreover, these cells are functional and specifically suppress primed T cells in vivo. Expression of soluble ICOS-Ig by a xenograft generates antigen specific CD4+ CD25+ Foxp3+ T cells that mediate specific graft prolongation using at least 3 key mediators: IL-10, perforin and granzyme B. This article is protected by copyright. All rights reserved.
DOI: 10.1111/tri.13474
ORCID: 0000-0002-8189-4952
Journal: Transplant international : official journal of the European Society for Organ Transplantation
PubMed URL: 31225919
Type: Journal Article
Subjects: IL-10
Inducible Co-Stimulator (ICOS)
T Cells
perforin and granzyme B
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