Peripherally Induced Tolerance Depends on Peripheral Regulatory T Cells That Require Hopx To Inhibit Intrinsic IL-2 Expression

Abstract

Dendritic Cells (DCs) can induce peripheral immune tolerance that prevents autoimmune responses. Antigen presentation by peripheral DCs under steady state conditions leads to a conversion of some peripheral CD4+ T cells into Treg cells that require Homeodomain Only Protein (Hopx) to mediate T cell unresponsiveness. However, the roles of these peripheral (p)Treg cells in averting autoimmune responses as well as immunological mechanisms of Hopx remain unknown. Here we report that Hopx+ pTreg cells converted by DCs from Hopxneg T cells are indispensible to sustain tolerance that prevents autoimmune responses directed at self-antigens during experimental acute encephalomyelitis (EAE). Our studies further reveal that Hopx inhibits intrinsic IL-2 expression in pTreg cells after antigenic re-challenge. In the absence of Hopx, increased levels of IL-2 lead to death and decreased numbers of pTreg cells. Therefore formation of Hopx+ pTreg cells represents a crucial pathway of sustained tolerance induced by peripheral DCs and the maintenance of such pTreg cells and tolerance requires functions of Hopx to block intrinsic IL-2 production in pTreg cells.

Dendritic Cells As Inducers of Peripheral Tolerance

“…Other studies found a similar extrathymic conversion by specialized CD103 + DCs presenting intestinal and food antigens within gut associated lymphoid tissues (GALT) of Foxp3 + Treg cells contributing to maintenance of local immune homeostasis [27, 28, 70–73]. Recent results of experiments in an EAE model using Hopx −/− mice that have specific deficiencies in functions and survival of pTreg cells (but not tTreg cells) helped to further establish the essential roles of pTreg cells in the maintenance of DC-induced tolerance and prevention of organ-specific autoimmunity [54, 74]. Overall, these results suggested that specialized tolerogenic DCs in steady state are not immature bystanders but rather inducers of active processes in T cells to promote mechanisms of peripheral tolerance including a conversion of pTreg cells.…”

“…Consistent with such actively induced mechanisms, various immune mediators and environmental signals including materials from dead cells and some microbial products may enhance tolerogenic properties of DCs as reviewed by Manicassamy and Pulendran in [75], Sancho and Reis e Sousa in [76] and Mellman in [37]. The specific tolerogenic mechanisms of such tolerogenic types of DCs and the roles of pTreg cells have become an area of intense investigation [37, 54, 68, 70, 71, 73, 77, 78]. …”

“…In the first of such experiments, DCs were targeted in vivo with anti-DEC205 chimeric antibody to deliver a potentially-encephalitogenic antigen, myelin oligodendrocyte glycoprotein (MOG), to prevent subsequently-induced EAE [32]. Further, these early results were thereafter extended to other EAE models using multiple encephalitogenic antigens delivered through diverse molecules expressed on both conventional and plasmacytoid DCs [52, 54, 55, 60, 106–108]. Such DC-induced protection from EAE was mediated by the crucial functions of the de novo induced pTreg cells [54].…”

“…Further, these early results were thereafter extended to other EAE models using multiple encephalitogenic antigens delivered through diverse molecules expressed on both conventional and plasmacytoid DCs [52, 54, 55, 60, 106–108]. Such DC-induced protection from EAE was mediated by the crucial functions of the de novo induced pTreg cells [54]. These results confirmed the paradigm that to avoid induction of autoimmunity, tolerance needs to be established before the immune system is challenged with specific antigens under the pro-inflammatory conditions.…”

Genetic-Epigenetic Interactions in Asthma Revealed by a Genome-Wide Gene-Centric Search

“…There is scant prior evidence of a role for these genes in pulmonary or immune function, lung disease, or asthma, although HOPX is involved in the function of regulatory T cells [52].…”