Abstract
Regulatory T cell (Treg) reconstitution is essential for reestablishing tolerance and maintaining homeostasis following stem-cell transplantation. We previously reported that bone marrow (BM) is highly enriched in autophagy-dependent Treg and autophagy disruption leads to a significant Treg loss, particularly BM-Treg. To correct the known Treg deficiency observed in chronic graft-versus-host disease (cGVHD) patients, low dose IL-2 infusion has been administered, substantially increasing peripheral Treg (pTreg) numbers. However, as clinical responses were only seen in ∼50% of patients, we postulated that pTreg augmentation was more robust than for BM-Treg. We show that BM-Treg and pTreg have distinct characteristics, indicated by differential transcriptome expression for chemokine receptors, transcription factors, cell cycle control of replication and genes linked to Treg function. Further, BM-Treg were more quiescent, expressed lower FoxP3, were highly enriched for co-inhibitory markers and more profoundly depleted than splenic Treg in cGVHD mice. In vivo our data are consistent with the BM and not splenic microenvironment is, at least in part, driving this BM-Treg signature, as adoptively transferred splenic Treg that entered the BM niche acquired a BM-Treg phenotype. Analyses identified upregulated expression of IL-9R, IL-33R, and IL-7R in BM-Treg. Administration of the T cell produced cytokine IL-2 was required by splenic Treg expansion but had no impact on BM-Treg, whereas the converse was true for IL-9 administration. Plasmacytoid dendritic cells (pDCs) within the BM also may contribute to BM-Treg maintenance. Using pDC-specific BDCA2-DTR mice in which diptheria toxin administration results in global pDC depletion, we demonstrate that pDC depletion hampers BM, but not splenic, Treg homeostasis. Together, these data provide evidence that BM-Treg and splenic Treg are phenotypically and functionally distinct and influenced by niche-specific mediators that selectively support their respective Treg populations. The unique properties of BM-Treg should be considered for new therapies to reconstitute Treg and reestablish tolerance following SCT.
Highlights
Regulatory T cells (Treg) are an immunosuppressive CD4+ T cell subset essential for immune regulation and maintaining self-tolerance
We have previously reported that the Treg population that resides in the BM is enriched with an autophagy-dependent TIGIT+ Treg population critical for establishing tolerance and controlling Graft-versus-host disease (GVHD) following stem cell transplantation (SCT) (Le Texier et al, 2016)
Regulatory T cell represent a diverse immunoregulatory regulatory population necessary for peripheral tolerance and immune homeostasis. This is evident within the setting of allogeneic SCT, where Treg have been shown to be critical for immune reconstitution and GVHD control
Summary
Regulatory T cells (Treg) are an immunosuppressive CD4+ T cell subset essential for immune regulation and maintaining self-tolerance. Graft-versus-host disease (GVHD) is a tissuedestructive process of immune dysfunction in patients following allogeneic stem cell transplantation (SCT) (Taylor et al, 2002; Rezvani et al, 2006; Robb et al, 2012; Zhang et al, 2013; Le Texier et al, 2017). As several major limitations impede the more widespread translation of Treg-based therapies (Brunstein et al, 2011; Hippen et al, 2011; Zhang et al, 2013; McDonald-Hyman et al, 2015; Koyama et al, 2016; Le Texier et al, 2016), clinical approaches have focused on increasing in vivo Treg number to promote immune tolerance flowing allogeneic SCT. As IL-2 binds the heterotrimer IL-2Ra,b,g, such therapy may activate and expand conventional T cells (Tcon) (Pérol et al, 2014; Kim et al, 2016) with the potential to exacerbate inflammation
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