MHC-Mismatched but Not Matched Mixed Chimerism Is Able to Restore Peripheral Tolerance for Non-Cross-Reactive Autoreactive T Cells in Diabetic NOD Mice

Presentation Number: LB SAT 79
Date of Presentation: April 1st, 2017

Mingfeng Zhang*, Jeremy Racine, Qing Lin, Yuqing Liu, Qi Qin, Arthur Riggs and Defu Zeng
Beckman Research Institute of City of Hope, Duarte, CA

Abstract

MHC-mismatched but not matched mixed chimerism reverses autoimmunity, with deletion of cross-reactive thymocytes. However, how MHC-mismatched mixed chimerism tolerizes non-cross-reactive autoreactive T cells remains unclear, especially since there are both cross- and non-cross-reactive autoreactive T cells in type 1 diabetic (T1D) NOD mice. In the current studies, by induction of mixed chimerism in Rag-1-/-BDC2.5 and Rag-1-/-BDC12-4.1 diabetic NOD mice that have only non-cross-reactive transgenic autoreactive T cells, we found: 1) No impact on the percentage of CD4+CD8+ thymocytes (no impact on negative selection). 2) MHC-mismatched but not matched mixed chimerism was able to markedly reduce Th1 effector cells and induce anergy of residual host-type T cells, as judged by surface markers (PD-1hiIL-7Rαlo), leading to marked reduction of insulitis and prevention of T1D. 3) Host-type plasmacytoid dendertic cells (pDCs) in the MHC-mismatched but not matched mixed chimeras showed marked upregulation of PD-L1 expression, which was associated with expansion of donor- and host-type Foxp3+ Treg cells. 4) Co-transfer of host- and donor-type T and Treg cells from the MHC-mismatched mixed chimeric Rag-1-/-BDC2.5 mice induced T1D in adoptive NOD-scid recipients but not in NOD-scid adoptive recipients with pre-engraftment of donor-type DCs. Donor-type Treg and donor-type DC expression of MHCII were both required for prevention of T1D in the adoptive recipients pre-engrafted with donor DCs. 5) Histoimmunofluorescent staining showed that donor Treg cells interact with both donor- and host-type DCs in the MHC-mismatched chimeras. These results suggest that donor-type Treg cells in the MHC-mismatched mixed chimeras are able to restore the tolerogenic status of host-type pDCs, which expend host-type Treg cells and control host-type non-cross-reactive T cells. Therefore, induction of MHC-mismatched mixed chimerism can re-establish a tolerogenic DC and Treg network in the periphery and tolerize non-cross-reactive autoreactive T cells.

 

Nothing to Disclose: MZ, JR, QL, YL, QQ, AR, DZ