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Direct IL-33 Stimulation of T Regulatory Cells via Suppression of Tumorigenicity 2 (ST2) Is Required for Effective Control of Alloimmune Responses.

X. Zhang,1,3 B. Matta,1 D. Reichenbach,2 B. Blazar,2 H. Turnquist.1

1Dept of Surgery, Starzl Transplantation Inst, Pittsburgh, PA
2Dept of Pediatrics, Univ of Minnesota, Minneapolis, MN
3Xiangya School of Medicine, Central South University, Changsha, Hunan, China.

Meeting: 2016 American Transplant Congress

Abstract number: 249

Keywords: Bone marrow transplantation, Graft-versus-host-disease, Lymphocytes, Mice

Session Information

Date: Monday, June 13, 2016

Session Name: Concurrent Session: Regulatory T Cells: Animal Models

Session Time: 2:30pm-4:00pm

 Presentation Time: 2:42pm-2:54pm

Location: Room 309

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Background: IL-33 is a pleotropic cytokine that can protect against cardiac transplant rejection by expanding regulatory T cells (Treg), particularly a Treg subset expressing the IL-33 receptor, Suppression of Tumorigenicity 2 (ST2). However, if IL-33-mediated signals directly impact on the ST2-expressing Treg expansion and alloimmune regulatory functions is poorly understood. The goals of this study was to precisely characterize IL-33-mediated Treg signaling and establish the importance of direct IL-33 stimulation of Treg for control of alloimmune responses.

Methods: To determine the importance of ST2 expression on Treg for regulation of alloimmune responses, we utilized a rodent model of graft-vs. host disease (GVHD) where C57BL/6 recipient mice were given lethal total body irradiation followed by a subsequent BALB/c bone marrow graft. Graft recipients also received wild-type (WT) BALB/c CD3+ effector T cells (Teff) alone, or with CD4+ CD25+ Treg from WT (st2+/+) or st2-/- mice (Treg:Teff=1:2). In related experiments, fluorescence activated cell sorting was used to obtain ST2– or ST2+ populations of Foxp3+ cells from the splenocytes of Foxp3 Reporter mice (FOXP3-IRES-mRFP mice). The capacity of IL-33 to activate signaling downstream of ST2 in each population was quantitated by phosphoflow cytometry.

Results: Where as 90% of recipients receiving st2+/+ CD4+ CD25+ were free of GVHD at Day 100 post-alloHCT, only 10% of mice that received st2-/- Treg survived long-term (p=0.0017, st2+/+ v. st2-/-). Associated mechanistic studies revealed that Treg frequency was reduced in recipients receiving st2–/- Treg cells compared to those receiving st2+/+ Treg. Phosphoflow established that IL-33 signaling via ST2+ on Treg activates both NF-κB and p38 MAPK. Yet, only IL-33-stimulation of p38 MAPK, but not NF-kB, was required for ST2+ Treg expansion.

Conclusions: These studies make the novel observation that IL-33 activates p38 MAPK to drive selective ST2+ Treg expansion. We also establish that IL-33-mediated ST2 signaling is critical to the capacity of adoptively transferred Treg to prevent the alloimmune responses leading to GVHD. In total, our data reveal the importance of IL-33 stimulation of Treg for effective regulation of alloimmunity.

CITATION INFORMATION: Zhang X, Matta B, Reichenbach D, Blazar B, Turnquist H. Direct IL-33 Stimulation of T Regulatory Cells via Suppression of Tumorigenicity 2 (ST2) Is Required for Effective Control of Alloimmune Responses. Am J Transplant. 2016;16 (suppl 3).

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To cite this abstract in AMA style:

Zhang X, Matta B, Reichenbach D, Blazar B, Turnquist H. Direct IL-33 Stimulation of T Regulatory Cells via Suppression of Tumorigenicity 2 (ST2) Is Required for Effective Control of Alloimmune Responses. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/direct-il-33-stimulation-of-t-regulatory-cells-via-suppression-of-tumorigenicity-2-st2-is-required-for-effective-control-of-alloimmune-responses/. Accessed March 7, 2021.

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