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CD40 provides immune privilege to the bone marrow hematopoietic niche

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Title:CD40 provides immune privilege to the bone marrow hematopoietic niche
Creators Name:Bassani, B. and Gulino, A. and Portararo, P. and Botti, L. and Cappetti, B. and Chiodoni, C. and Bolli, N. and Ciciarello, M. and Joehrens, K. and Anagnostopoulos, I. and Na, I.K. and Curti, A. and Tripodo, C. and Colombo, M.P. and Sangaletti, S.
Abstract:Allogeneic bone marrow transplantation remains the only therapeutic option for a wide range of hematological malignancies despite the risk of possible adverse, immune-related events, such as infection and acute graft-versus-host disease (aGVHD). aGVHD is characterized by T-cell activation, defective B-cell development and osteoblastic niche destruction in bone marrow (BM) among other issues. Transplant conditioning regimens cause excessive inflammatory cytokines production and impaired regulatory T-cell control of aberrant T-cell activation. Here, we show that mesenchymal cells (MSCs) upregulated CD40 upon irradiation at the expense of mesenchymal markers, and that CD40 endows MSC of regulatory function on Treg homeostasis and fitness. Transplantation of wild type hematopoietic cells into a CD40-null recipient reduces Treg numbers allowing persistent T-cell activation and pro-inflammatory cytokines production causing, impaired B-lymphopoiesis. These evidences find correlation in aGVHD patients showing the loss of CD40+ BM-MSCs along with reduction in cells of the B-lineage. Modeling aGVHD in mice we show that the elimination of CD40+ BM-MSCs relies on their higher expression of MHC-I molecules. Indeed, aGVHD mice compared to MHC-matched controls showed the loss of MHC-I + radio-resistant host BM-MSCs. Our data point to CD40+ MHC-I+BM-MSCs as a key regulator of BM tolerogenic niches.
Keywords:Animals, Mice
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2020.08.10.243691
Date:10 August 2020
Official Publication:https://doi.org/10.1101/2020.08.10.243691

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