AUTHOR=Liu Yi-Hsia , Mölzer Christine , Makinen Kimmo , Kamoi Koju , Corbett Clare L. C. , Klaska Izabela P. , Reid Delyth M. , Wilson Heather M. , Kuffová Lucia , Cornall Richard J. , Forrester John V. 

TITLE=Treatment With FoxP3+ Antigen-Experienced T Regulatory Cells Arrests Progressive Retinal Damage in a Spontaneous Model of Uveitis

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.02071

DOI=10.3389/fimmu.2020.02071

ISSN=1664-3224

ABSTRACT=<p>We specify the clinical features of a spontaneous experimental autoimmune uveitis (EAU) model, in which foreign hen-egg lysozyme (HEL) is expressed in the retina, controlled by the promoter for interphotoreceptor retinol binding protein (IRBP). We previously reported 100% P21 (post-partum day) IRBP:HEL single transgenic (sTg) mice, when crossed to transgenic T cell receptor mice (3A9) generating the double transgenic (dTg) genotype, develop EAU despite profound lymphopenia (thymic HEL-specific T cell deletion). In this work, we characterized the immune component of this model and found conventional dTg CD4+ T cells were less anergic than those from 3A9 controls. Furthermore, prior <italic>in vitro</italic> HEL-activation of 3A9 anergic T cells (T<sub>an</sub>) rendered them uveitogenic upon adoptive transfer (Tx) to sTg mice, while antigen-experienced (AgX, dTg), but not naïve (3A9) T cells halted disease in P21 dTg mice. Flow cytometric analysis of the AgX cells elucidated the underlying pathology: FoxP3+CD25<sup>hi</sup>CD4+ T regulatory cells (T<sub>reg</sub>) comprised ∼18%, while FR4+CD73+FoxP3-CD25<sup>lo/–</sup>CD4+ T<sub>an</sub> comprised ∼1.2% of total cells. Further T<sub>reg</sub>-enrichment (∼80%) of the AgX population indicated FoxP3+CD25<sup>hi</sup>CD4+ T<sub>reg</sub> played a key role in EAU-suppression while FoxP3-CD25<sup>lo/–</sup>CD4+ T cells did not. Here we present the novel concept of dual immunological tolerance where spontaneous EAU is due to escape from anergy with consequent failure of T<sub>reg</sub> induction and subsequent imbalance in the [T<sub>reg</sub>:T<sub>effector</sub>] cell ratio. The reduced numbers of T<sub>an</sub>, normally sustaining T<sub>reg</sub> to prevent autoimmunity, are the trigger for disease, while immune homeostasis can be restored by supplementation with AgX, but not naïve, antigen-specific T<sub>reg</sub>.</p>