MHC-mismatched Mixed Chimerism Restores Peripheral Tolerance of Noncross-reactive Autoreactive T Cells in NOD Mice

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2018 Feb 22

PMID 29463744

Citations 7

Authors

Mingfeng Zhang

Jeremy J Racine

Qing Lin

Yuqing Liu

Shanshan Tang

Qi Qin

Tong Qi

Arthur D Riggs

Defu Zeng

Affiliations

Soon will be listed here.

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.Rag1BDC2.5 or NOD.Rag1BDC12-4.1 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.

Citing Articles

Advances in hematopoietic stem cell transplantation for autoimmune diseases.

Xu Y, Wang X, Hu Z, Huang R, Yang G, Wang R Heliyon. 2024; 10(20):e39302.

PMID: 39492896 PMC: 11530805. DOI: 10.1016/j.heliyon.2024.e39302.

Improving thymus implantation for congenital athymia with interleukin-7.

Min H, Valente L, Xu L, ONeil S, Begg L, Kurtzberg J Clin Transl Immunology. 2023; 12(11):e1475.

PMID: 38020730 PMC: 10665642. DOI: 10.1002/cti2.1475.

The screening, identification, design and clinical application of tumor-specific neoantigens for TCR-T cells.

Li J, Xiao Z, Wang D, Jia L, Nie S, Zeng X Mol Cancer. 2023; 22(1):141.

PMID: 37649123 PMC: 10466891. DOI: 10.1186/s12943-023-01844-5.

Murine Models Provide New Insights Into Pathogenesis of Chronic Graft--Host Disease in Humans.

Song Q, Kong X, Martin P, Zeng D Front Immunol. 2021; 12:700857.

PMID: 34539630 PMC: 8446193. DOI: 10.3389/fimmu.2021.700857.

Hematopoietic Stem Cells in Type 1 Diabetes.

Pastore I, Assi E, Ben Nasr M, Bolla A, Maestroni A, Usuelli V Front Immunol. 2021; 12:694118.

PMID: 34305929 PMC: 8299361. DOI: 10.3389/fimmu.2021.694118.

References

Tokita D, Mazariegos G, Zahorchak A, Chien N, Abe M, Raimondi G . High PD-L1/CD86 ratio on plasmacytoid dendritic cells correlates with elevated T-regulatory cells in liver transplant tolerance. Transplantation. 2008; 85(3):369-77. DOI: 10.1097/TP.0b013e3181612ded. View

Deng R, Cassady K, Li X, Yao S, Zhang M, Racine J . B7H1/CD80 interaction augments PD-1-dependent T cell apoptosis and ameliorates graft-versus-host disease. J Immunol. 2014; 194(2):560-74. PMC: 4282988. DOI: 10.4049/jimmunol.1402157. View

Li Q, Xu B, Michie S, Rubins K, Schreriber R, McDevitt H . Interferon-alpha initiates type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci U S A. 2008; 105(34):12439-44. PMC: 2527930. DOI: 10.1073/pnas.0806439105. View

Sewell A . Why must T cells be cross-reactive?. Nat Rev Immunol. 2012; 12(9):669-77. PMC: 7097784. DOI: 10.1038/nri3279. View

Swiecki M, Colonna M . Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol Rev. 2010; 234(1):142-62. PMC: 3507434. DOI: 10.1111/j.0105-2896.2009.00881.x. View

Stadinski B, Delong T, Reisdorph N, Reisdorph R, Powell R, Armstrong M . Chromogranin A is an autoantigen in type 1 diabetes. Nat Immunol. 2010; 11(3):225-31. PMC: 3166626. DOI: 10.1038/ni.1844. View

McGinty J, Chow I, Greenbaum C, Odegard J, Kwok W, James E . Recognition of posttranslationally modified GAD65 epitopes in subjects with type 1 diabetes. Diabetes. 2014; 63(9):3033-40. PMC: 4392921. DOI: 10.2337/db13-1952. View

Nejentsev S, Howson J, Walker N, Szeszko J, Field S, Stevens H . Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature. 2007; 450(7171):887-92. PMC: 2703779. DOI: 10.1038/nature06406. View

Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D . Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature. 2005; 435(7039):220-3. PMC: 1364531. DOI: 10.1038/nature03523. View

10.

Wang L, Pino-Lagos K, de Vries V, Guleria I, Sayegh M, Noelle R . Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci U S A. 2008; 105(27):9331-6. PMC: 2442817. DOI: 10.1073/pnas.0710441105. View

11.

Thornton A, Korty P, Tran D, Wohlfert E, Murray P, Belkaid Y . Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol. 2010; 184(7):3433-41. PMC: 3725574. DOI: 10.4049/jimmunol.0904028. View

12.

Fousteri G, Jasinski J, Dave A, Nakayama M, Pagni P, Lambolez F . Following the fate of one insulin-reactive CD4 T cell: conversion into Teffs and Tregs in the periphery controls diabetes in NOD mice. Diabetes. 2012; 61(5):1169-79. PMC: 3331775. DOI: 10.2337/db11-0671. View

13.

Racine J, Wang M, Zhang C, Lin C, Liu H, Todorov I . Induction of mixed chimerism with MHC-mismatched but not matched bone marrow transplants results in thymic deletion of host-type autoreactive T-cells in NOD mice. Diabetes. 2011; 60(2):555-64. PMC: 3028355. DOI: 10.2337/db10-0827. View

14.

Pearson J, Wong F, Wen L . The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes. J Autoimmun. 2015; 66:76-88. PMC: 4765310. DOI: 10.1016/j.jaut.2015.08.019. View

15.

Ganguly D, Haak S, Sisirak V, Reizis B . The role of dendritic cells in autoimmunity. Nat Rev Immunol. 2013; 13(8):566-77. PMC: 4160805. DOI: 10.1038/nri3477. View

16.

Malmegrim K, de Azevedo J, Arruda L, Abreu J, Couri C, de Oliveira G . Immunological Balance Is Associated with Clinical Outcome after Autologous Hematopoietic Stem Cell Transplantation in Type 1 Diabetes. Front Immunol. 2017; 8:167. PMC: 5319960. DOI: 10.3389/fimmu.2017.00167. View

17.

Racine J, Wang M, Zhang M, Zeng D . Induction of mixed chimerism depletes pre-existing and de novo-developed autoreactive B cells in autoimmune NOD mice. Diabetes. 2014; 63(6):2051-62. DOI: 10.2337/db13-1532. View

18.

Delong T, Wiles T, Baker R, Bradley B, Barbour G, Reisdorph R . Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science. 2016; 351(6274):711-4. PMC: 4884646. DOI: 10.1126/science.aad2791. View

19.

Wherry E . T cell exhaustion. Nat Immunol. 2011; 12(6):492-9. DOI: 10.1038/ni.2035. View

20.

Chen W, Liang X, Peterson A, Munn D, Blazar B . The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol. 2008; 181(8):5396-404. PMC: 2614675. DOI: 10.4049/jimmunol.181.8.5396. View