Early CD30 Signaling Is Critical for Adoptively Transferred CD4+CD25+ Regulatory T Cells in Prevention of Acute Graft Versus Host Disease.

Abstract

CD4+CD25+ regulatory T cells (Treg) have been demonstrated to reduce the severity of acute graft-versus-host disease (aGvHD) in murine models of bone marrow transplantation. However, the surface molecules that are critical for suppression are unclear. The TNF-R superfamily member CD30 has been shown to be expressed on regulatory T cells that down-modulate nickel specific immune responses and to be relevant for Treg mediated protection from allograft rejection. Deficiency of the CD30 molecule (CD30−/−) is associated with impaired thymic negative selection and augmented T cell autoreactivity. Therefore, we investigated the role of CD30 signaling in Treg function in an aGvHD model. Treg derived from CD30−/ − animals were significantly less effective in preventing aGvHD lethality (wt vs. CD30−/ − p=0.002). Signal intensity derived from expanding luciferase expressing alloreactive conventional T cells (Tconv) was significantly higher if CD30−/ − Treg as compared to wt Treg (p=0.007) were transferred as assessed by bioluminescencent based imaging. Blockade of the CD30/CD153 pathway with a neutralizing anti-CD153 mAb during the early (days −2 to +4) but not late (days +4 to +10) phase of adoptive Treg transfer reduced Treg mediated protection from proinflammatory cytokine accumulation and apoptosis of donor-type CD4 and CD8 T cells. In vivo bioluminescence imaging demonstrated intact Treg homing, but reduced expansion when CD153 was blocked during the early phase after adoptive transfer. CD30 surface expression on Treg increased with alloantigen exposure and CD153 expression on recipient-type dendritic cells increased in the presence of an irradiation induced proinflammatory environment but not when T cell depleted bone marrow and Tconv were transferred into non-irradiated Rag 2−/ −γc−/ − recipients. These data are the first to demonstrate that early CD30 signaling is relevant for Treg mediated aGvHD protection after major MHC mismatch bone marrow transplantation.