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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.

Author information

1
Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, CA 91010.
2
Hematologic Malignancies and Stem Cell Transplantation Institute, The Beckman Research Institute of City of Hope, Duarte, CA 91010.
3
Department of Clinical Laboratory, People's Hospital Affiliated to Fujian Traditional Chinese Medicine University, 350004 Fuzhou, China.
4
Department of Hematology, Xinqiao Hospital, The Army Medical University, 400000 Chongqing, China.
5
State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 210009 Nanjing, China.
6
Eugene and Ruth Roberts Summer Student Academy, City of Hope, Duarte, CA 91010.
7
Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, CA 91010; ariggs@coh.org dzeng@coh.org.

Abstract

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.

KEYWORDS:

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

PMID:
29463744
PMCID:
PMC5877958
DOI:
10.1073/pnas.1720169115
[Indexed for MEDLINE]
Free PMC Article

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