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
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).
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 July 5, 2020.
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