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Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity.

ABSTRACT: TNF is a multifunctional cytokine involved in autoimmune disease pathogenesis that exerts its effects through two distinct TNF receptors, TNFR1 and TNFR2. While TNF- and TNFR1-deficient (but not TNFR2-deficient) mice show very similar phenotypes, the significance of TNFR2 signaling in health and disease remains incompletely understood. Recent studies implicated the importance of the TNF/TNFR2 axis in T regulatory (T_reg) cell functions. To definitively ascertain the significance of TNFR2 signaling, we generated and validated doubly humanized TNF/TNFR2 mice, with the option of conditional inactivation of TNFR2. These mice carry a functional human TNF-TNFR2 (hTNF-hTNFR2) signaling module and provide a useful tool for comparative evaluation of TNF-directed biologics. Conditional inactivation of TNFR2 in FoxP3⁺ cells in doubly humanized TNF/TNFR2 mice down-regulated the expression of T_reg signature molecules (such as FoxP3, CD25, CTLA-4, and GITR) and diminished T_reg suppressive function in vitro. Consequently, T_reg-restricted TNFR2 deficiency led to significant exacerbation of experimental autoimmune encephalomyelitis (EAE), accompanied by reduced capacity to control Th17-mediated immune responses. Our findings expose the intrinsic and beneficial effects of TNFR2 signaling in T_reg cells that could translate into protective functions in vivo, including treatment of autoimmunity.

SUBMITTER: Atretkhany KN

PROVIDER: S-EPMC6304938 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity.

Atretkhany Kamar-Sulu N KN Mufazalov Ilgiz A IA Dunst Josefine J Kuchmiy Anna A Gogoleva Violetta S VS Andruszewski David D Drutskaya Marina S MS Faustman Denise L DL Schwabenland Marius M Prinz Marco M Kruglov Andrey A AA Waisman Ari A Nedospasov Sergei A SA

Proceedings of the National Academy of Sciences of the United States of America 20181129 51

TNF is a multifunctional cytokine involved in autoimmune disease pathogenesis that exerts its effects through two distinct TNF receptors, TNFR1 and TNFR2. While TNF- and TNFR1-deficient (but not TNFR2-deficient) mice show very similar phenotypes, the significance of TNFR2 signaling in health and disease remains incompletely understood. Recent studies implicated the importance of the TNF/TNFR2 axis in T regulatory (T<sub>reg</sub>) cell functions. To definitively ascertain the significance of TNF ...[more]

PMID: 30498033

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Project description:Susceptibility and protection against human autoimmune diseases, including type I diabetes, multiple sclerosis, and Goodpasture disease, is associated with particular human leukocyte antigen (HLA) alleles. However, the mechanisms underpinning such HLA-mediated effects on self-tolerance remain unclear. Here we investigate the molecular mechanism of Goodpasture disease, an HLA-linked autoimmune renal disorder characterized by an immunodominant CD4+ T-cell self-epitope derived from the ?3 chain of type IV collagen (?3135-145). While HLA-DR15 confers a markedly increased disease risk, the protective HLA-DR1 allele is dominantly protective in trans with HLA-DR15 (ref. 2). We show that autoreactive ?3135-145-specific T cells expand in patients with Goodpasture disease and, in ?3135-145-immunized HLA-DR15 transgenic mice, ?3135-145-specific T cells infiltrate the kidney and mice develop Goodpasture disease. HLA-DR15 and HLA-DR1 exhibit distinct peptide repertoires and binding preferences and present the ?3135-145 epitope in different binding registers. HLA-DR15-?3135-145 tetramer+ T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-?3135-145 tetramer+ T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4+Foxp3+ regulatory T cells (Treg cells) expressing tolerogenic cytokines. HLA-DR1-induced Treg cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15+ and HLA-DR1+ healthy human donors display altered ?3135-145-specific T-cell antigen receptor usage, HLA-DR15-?3135-145 tetramer+ Foxp3- Tconv and HLA-DR1-?3135-145 tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded ?3135-145-specific CD4+ T-cell repertoire. Accordingly, we provide a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease, whereby HLA polymorphism shapes the relative abundance of self-epitope specific Treg cells that leads to protection or causation of autoimmunity.

Dataset Information

Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity.

Publications

Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity.

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