Role of bone marrow Tregs in maintaining stromal cell function

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PROJECT SUMMARY / ABSTRACT Regulatory T cells (Tregs) are known for not only their ability to regulate immune response, but also for their heterogeneity and non-canonical functions in tissue maintenance. As recently suggested tissue-specific Tregs have specialized functions to maintain those tissues in which they exist, and in adipose tissue, lung, and skin function to support local tissue stem cells. Accumulating evidence suggests that the stromal microenvironment regulates immune response; we propose that the reverse is also true, specifically through marrow Treg and stromal cell interactions. Interestingly, Tregs represent approximately one-third of all CD4+ T lineage cells in the marrow, a portion that is significantly higher than other hematopoietic tissues; however, the function of tissue resident Tregs in the maintenance of the bone microenvironment and underlying molecular signature remain unclear. Our focus is to uncover the signaling pathways that marrow Treg use to maintain mesenchymal stromal cell's differentiation and hematopoietic stem cells support. We have found that depletion of Tregs alters the bone marrow microenvironment, and more specifically increases cycling and alters differentiation of mesenchymal stromal cells. Based on our preliminary data, we propose that marrow Tregs are a unique subpopulation of immune cells with preferential bias to circulate back to the bone marrow and this is supported by their unique chemokine and cytokine receptor profile. Our research identifies Tregs as the major source of interleukin-10 (IL-10) in the marrow; and support a role for Treg-secreted IL-10 as a main factor that supports stromal cell functions. In ongoing studies, we are trying to define the IL-10 specific mechanisms of stromal cell maintenance. We propose to define how IL-10 signaling pathways in stromal cells support their maintenance (Aim 1). We will characterize the function and transcriptional characteristics of marrow stromal cells using stromal cell fate-mapping mouse models following IL-10 and Treg perturbation to define the molecular drivers for maintenance during hematopoietic stem cell transplants (Aim 2). We expect that these experiments will define new regulatory networks by establishing bi-directional communication between highly specialized tissue-resident lymphocytes and marrow stromal cells. These results will provide the basis for studies to understand how infections, transplantation, or disease may impact these interactions. We will exploit these interactions to impede pre-malignant clones by altering the marrow microenvironment (Aim 3). Moving forward, these findings could lead to therapeutic targets for improved bone marrow transplantation or changing outcomes in hematopoietic disease.