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MHC-mismatched mixed chimerism restores peripheral tolerance of noncross-reactive
autoreactive T cells in NOD mice
#MMPMID29463744
Zhang M
; Racine JJ
; Lin Q
; Liu Y
; Tang S
; Qin Q
; Qi T
; Riggs AD
; Zeng D
Proc Natl Acad Sci U S A
2018[Mar]; 115
(10
): E2329-E2337
PMID29463744
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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.
|*Major Histocompatibility Complex
[MESH]
|*Peripheral Tolerance
[MESH]
|Animals
[MESH]
|Autoimmunity
[MESH]
|Diabetes Mellitus, Type 1/*genetics/immunology/therapy
[MESH]
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