Abstract
The nonimmune roles of Tregs have been described in various tissues, including the BM. In this study, we comprehensively phenotyped marrow Tregs, elucidating their key features and tissue-specific functions. We show that marrow Tregs are migratory and home back to the marrow. For trafficking, marrow Tregs use S1P gradients, and disruption of this axis allows for specific targeting of the marrow Treg pool. Following Treg depletion, the function and phenotype of both mesenchymal stromal cells (MSCs) and hematopoietic stem cells (HSCs) was impaired. Transplantation also revealed that a Treg-depleted niche has a reduced capacity to support hematopoiesis. Finally, we found that marrow Tregs are high producers of IL-10 and that Treg-secreted IL-10 has direct effects on MSC function. This is the first report to our knowledge revealing that Treg-secreted IL-10 is necessary for stromal cell maintenance, and our work outlines an alternative mechanism by which this cytokine regulates hematopoiesis.
Highlights
Tregs are required for the preservation of immunological homeostasis
To evaluate the tissue-specific functions of BM Tregs, we compared their distribution to Tregs in other tissues: spleen and inguinal lymph node (LN)
Our results demonstrate that CD127 is an intrinsic characteristic of marrow Tregs and that IL-7 signaling may represent an adaptive mechanism in a context where IL-7 is the prevalent cytokine
Summary
Tregs are required for the preservation of immunological homeostasis. Recent work has shown that Tregs reside within specific tissues and contribute to nonimmune regulation of their local microenvironments [1,2,3,4,5,6]. Tregs have specialized roles in tissue regeneration, oral tolerance, and metabolic responses reflecting the functional and molecular heterogeneity of these cells [1, 7] These “tissue Tregs” are enriched at various sites, including skeletal muscle, epithelium, lamina propria, and adipose tissue [3, 4, 6, 8,9,10,11]. Tregs have been shown to play a critical role in improving graft versus host disease (GVHD) and recovery following BM transplantation [16,17,18] These observations indicate that Tregs are active regulators of homeostasis within the BM
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