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Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):E2329-E2337. doi: 10.1073/pnas.1720169115. Epub 2018 Feb 20.

MHC-mismatched mixed chimerism restores peripheral tolerance of noncross-reactive autoreactive T cells in NOD mice.

Zhang M1,2, Racine JJ1,2, Lin Q1,3, Liu Y1,4, Tang S1,5, Qin Q1,2, Qi T6, Riggs AD7, Zeng D7,2.

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Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, CA 91010.
Hematologic Malignancies and Stem Cell Transplantation Institute, The Beckman Research Institute of City of Hope, Duarte, CA 91010.
Department of Clinical Laboratory, People's Hospital Affiliated to Fujian Traditional Chinese Medicine University, 350004 Fuzhou, China.
Department of Hematology, Xinqiao Hospital, The Army Medical University, 400000 Chongqing, China.
State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 210009 Nanjing, China.
Eugene and Ruth Roberts Summer Student Academy, City of Hope, Duarte, CA 91010.
Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, CA 91010;


Autoimmune type 1 diabetes (T1D) and other autoimmune diseases are associated with particular MHC haplotypes and expansion of autoreactive T cells. Induction of MHC-mismatched but not -matched mixed chimerism by hematopoietic cell transplantation effectively reverses autoimmunity in diabetic nonobese diabetic (NOD) mice, even those with established diabetes. As expected, MHC-mismatched mixed chimerism mediates deletion in the thymus of host-type autoreactive T cells that have T-cell receptor (TCR) recognizing (cross-reacting with) donor-type antigen presenting cells (APCs), which have come to reside in the thymus. However, how MHC-mismatched mixed chimerism tolerizes host autoreactive T cells that recognize only self-MHC-peptide complexes remains unknown. Here, using NOD.Rag1-/-BDC2.5 or NOD.Rag1-/-BDC12-4.1 mice that have only noncross-reactive transgenic autoreactive T cells, we show that induction of MHC-mismatched but not -matched mixed chimerism restores immune tolerance of peripheral noncross-reactive autoreactive T cells. MHC-mismatched mixed chimerism results in increased percentages of both donor- and host-type Foxp3+ Treg cells and up-regulated expression of programmed death-ligand 1 (PD-L1) by host-type plasmacytoid dendritic cells (pDCs). Furthermore, adoptive transfer experiments showed that engraftment of donor-type dendritic cells (DCs) and expansion of donor-type Treg cells are required for tolerizing the noncross-reactive autoreactive T cells in the periphery, which are in association with up-regulation of host-type DC expression of PD-L1 and increased percentage of host-type Treg cells. Thus, induction of MHC-mismatched mixed chimerism may establish a peripheral tolerogenic DC and Treg network that actively tolerizes autoreactive T cells, even those with no TCR recognition of the donor APCs.


autoreactive T cells; hematopoietic cell transplantation; mixed chimerism; peripheral tolerance; type 1 diabetes

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