Premium
IL‐33 drives the production of mouse regulatory T cells with enhanced in vivo suppressive activity in skin transplantation
Author(s) -
Kawai Kento,
Uchiyama Masateru,
Hester Joanna,
Issa Fadi
Publication year - 2021
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.16266
Subject(s) - downregulation and upregulation , homing (biology) , immune system , in vivo , immunology , transplantation , medicine , chemokine , cytokine , regulatory t cell , cancer research , t cell , biology , il 2 receptor , gene , ecology , biochemistry , microbiology and biotechnology
Regulatory T cells (Tregs) are crucial mediators of immune homeostasis with the ability to modulate allogeneic response and control transplant rejection. Although Treg‐based cell therapies have shown immense promise, methods to optimize current strategies are critical for successful implementation within the clinic. IL‐33 is a cytokine with pleiotropic properties and effects on Treg function and development. In this study, we explored the unique properties of Treg populations activated through the IL‐33/ST2 pathway, aiming to exploit their tolerogenic properties for cell therapy. We show that treatment with exogenous IL‐33 results in a generalized downregulation of genes critical to T cell biology together with an upregulation of Treg‐associated genes. Tregs that develop in response to IL‐33 upregulate critical Treg‐associated markers, yet without developing enhanced in vitro suppressive capacity. Conversely, these Tregs display potent regulatory activity in vivo, promoting long‐term skin allograft survival in a stringent transplantation model. Detailed transcriptomic and immunophenotypic analyses of IL‐33–expanded Tregs reveal an enhancement in graft‐homing chemokine receptors, which may be partly responsible for their superior in vivo activity that is not reflected in vitro. IL‐33 treatment is therefore an attractive adjunctive strategy for patients receiving Treg cell therapeutics.