Antidiabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T cells into FOXP3<sup>+</sup>regulatory T cells

Tsai, Sue; Serra, Paul; Clemente-Casares, Xavier; Yamanouchi, Jun; Thiessen, Shari; Slattery, Robyn Maree; Elliott, John F.; Santamaría, Pere

doi:10.1073/pnas.1211391110

Cited by 17 publications

(30 citation statements)

References 40 publications

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“…Consistently, we also observed that in chronic graft versus host disease (GVHD) recipients, there were alloreactive CD4 + T clones that possess autoreactivity and mediate autoimmune-like chronic GVHD (41). Our observations are also consistent with others' reports that autoreactive or alloreactive T cells can express promiscuous TCRs that are capable of responding to more than one Ag (13,(42)(43)(44)(45). In addition, recent reports indicate that some autoreactive T cells can express more than one TCR as a means of surviving thymic negative selection (46).…”

Section: Discussionsupporting

confidence: 81%

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

Wang

Racine

Zhang

et al. 2014

The Journal of Immunology

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In nonautoimmune recipients, induction of mixed and complete chimerism with hematopoietic progenitor cells from MHC (HLA)-matched or -mismatched donors are effective approaches for induction of organ transplantation immune tolerance in both animal models and patients. But it is still unclear whether this is the case in autoimmune recipients. With the autoimmune diabetic NOD mouse model, we report that, although mixed and complete MHC-mismatched chimerism provide immune tolerance to donor-type islet and skin transplants, neither mixed nor complete MHC-matched chimerism does. The MHC-mismatched chimerism not only tolerizes the de novo developed, but also the residual pre-existing host-type T cells in a mismatched MHC class II–dependent manner. In the MHC-mismatched chimeras, the residual host-type peripheral T cells appear to be anergic with upregulation of PD-1 and downregulation of IL-7Rα. Conversely, in the MHC-matched chimeras, the residual host-type peripheral T cells manifest both alloreactivity and autoreactivity; they not only mediate insulitis and sialitis in the recipient, but also reject allogeneic donor-type islet and skin grafts. Interestingly, transgenic autoreactive BDC2.5 T cells from Rag1+/+, but not from Rag1−/−, NOD mice show alloreactivity and mediate both insulitis and rejection of allografts. Taken together, MHC-mismatched, but not MHC-matched, chimerism can effectively provide transplantation immune tolerance in autoimmune recipients.

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Section: Discussionsupporting

confidence: 81%

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

Wang

Racine

Zhang

et al. 2014

The Journal of Immunology

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“…Using two different, T1D-relevant TCR-transgenic NOD models, we show that I-E expression on DCs does not have intrinsic effects on DC function, on I-A (47). The preferential accumulation of these I-E-induced Tregs in the PLNs support the idea that these Tregs are b cell-autoreactive, hence, retained by PLN-associated, autoantigen-loaded APCs.…”

Section: Discussionsupporting

confidence: 52%

“…We have recently shown that the antidiabetogenic effects of another MHC class II molecule, I-A b , requires that it be expressed on DCs and macrophages but not B cells or thymic epithelial cells (47). This prompted us to ask whether the antidiabetogenic ability of I-E might also be mediated via DCs.…”

Section: I-ea K Affords T1d Resistance Exclusively Via Dcsmentioning

confidence: 99%

Dendritic Cell–Dependent In Vivo Generation of Autoregulatory T Cells by Antidiabetogenic MHC Class II

Tsai

Serra

Clemente-Casares

et al. 2013

The Journal of Immunology

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Several mechanisms have been proposed to explain how certain MHC class II molecules afford dominant resistance to autoimmune diseases like type 1 diabetes (T1D). However, it remains unclear how protective MHC types can blunt autoreactive T cell responses directed against a diverse repertoire of autoantigenic epitopes presented by disease-promoting MHCs. In this study, we show that expression of I-E on dendritic cells (DCs) of NOD mice promotes the differentiation of MHC promiscuous autoreactive CD4+ clonotypes into antidiabetogenic autoregulatory T cells. We expressed an I-EαkloxP transgene in NOD mice and used cell type–specific I-E ablation to show that I-E–expressing DCs, but not B cells, promote the generation of autoreactive CD4+Foxp3+ regulatory T cells (Tregs) and their accumulation in the pancreas-draining lymph nodes. There, these Tregs suppress the presentation of β cell Ags to naive autoreactive CD4+ and CD8+ T cells restricted by diabetogenic MHC molecules in an I-E–independent manner. Whereas selective removal of I-E on DCs abrogated autoregulatory Treg formation and T1D protection, selective removal of I-E on B cells was inconsequential. These results explain how certain MHC class II molecules can completely suppress antigenically complex autoimmune responses in an Ag-nonspecific manner.

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“…Another process that likely bears the brunt of such alteration is negative selection; this is supported by observations made in animal studies comparing disease-promoting MHCs to their disease-protective counterparts differing by only a few amino acids at positions located in the peptide-binding groove. In these studies, protective class II molecules curbed autoimmunity by promoting the negative selection of certain, in this case class II-promiscuous, autoreactive T-cell specificities (34–38). The latter observations brought forth the idea that protective class II polymorphisms located at or near the peptide-binding groove may be recognized by certain MHC-promiscuous autoreactive TCRs with an avidity and/or affinity above the threshold required for negative selection.…”

Section: Mhc Polymorphism and Positive/negative Selectionmentioning

confidence: 99%

MHC Class II Polymorphisms, Autoreactive T-Cells, and Autoimmunity

Tsai¹,

Santamaría²

2013

Front. Immunol.

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Major histocompatibility complex (MHC) genes, also known as human leukocyte antigen genes (HLA) in humans, are the prevailing contributors of genetic susceptibility to autoimmune diseases such as Type 1 Diabetes (T1D), multiple sclerosis, and rheumatoid arthritis, among others (1–3). Although the pathways through which MHC molecules afford autoimmune risk or resistance remain to be fully mapped out, it is generally accepted that they do so by shaping the central and peripheral T-cell repertoires of the host toward autoimmune proclivity or resistance, respectively. Disease-predisposing MHC alleles would both spare autoreactive thymocytes from central tolerance and bias their development toward a pathogenic phenotype. Protective MHC alleles, on the other hand, would promote central deletion of autoreactive thymocytes and skew their development toward non-pathogenic phenotypes. This interpretation of the data is at odds with two other observations: that in MHC-heterozygous individuals, resistance is dominant over susceptibility; and that it is difficult to understand how deletion of one or a few clonal autoreactive T-cell types would suffice to curb autoimmune responses driven by hundreds if not thousands of autoreactive T-cell specificities. This review provides an update on current advances in our understanding of the mechanisms underlying MHC class II-associated autoimmune disease susceptibility and/or resistance and attempts to reconcile these seemingly opposing concepts.

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Antidiabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T cells into FOXP3⁺regulatory T cells

Cited by 17 publications

References 40 publications

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

Dendritic Cell–Dependent In Vivo Generation of Autoregulatory T Cells by Antidiabetogenic MHC Class II

MHC Class II Polymorphisms, Autoreactive T-Cells, and Autoimmunity

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Antidiabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T cells into FOXP3+regulatory T cells

Cited by 17 publications

References 40 publications

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

Dendritic Cell–Dependent In Vivo Generation of Autoregulatory T Cells by Antidiabetogenic MHC Class II

MHC Class II Polymorphisms, Autoreactive T-Cells, and Autoimmunity

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Product

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Antidiabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T cells into FOXP3⁺regulatory T cells