Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells

Joshua D Ooi, Jan Petersen, Yu H Tan, Megan Huynh, Zoe J Willett, Sri H Ramarathinam, Peter J Eggenhuizen, Khai L Loh, Katherine A Watson, Poh Y Gan, Maliha A Alikhan, Nadine L Dudek, Andreas Handel, Billy G Hudson, Lars Fugger, David A Power, Stephen G Holt, P Toby Coates, Jon W Gregersen, Anthony W PurcellStephen R Holdsworth, Nicole L La Gruta, Hugh H Reid, Jamie Rossjohn, A Richard Kitching

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Abstract

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 selfepitope derived from the a3 chain of type IV collagen (a3135-145)1-4. 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 a3135-145-specific T cells expand in patients with Goodpasture disease and, in a3135-145- immunized HLA-DR15 transgenic mice, a3135-145-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 a3135-145 epitope in different binding registers. HLA-DR15-a3135-145 tetramer+ T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (Tconv) that secretes pro-inflammatory cytokines. In contrast, HLADR1- a3135-145 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 a3135-145-specific T-cell antigen receptor usage, HLADR15- a3135-145 tetramer+ Foxp3- Tconv and HLA-DR1-a3135-145 tetramer+ Foxp3+CD25hiCD127lo Treg dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded a3135-145-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.

OriginalsprogEngelsk
TidsskriftNature
Vol/bind545
Nummer7653
Sider (fra-til)243-247
Antal sider5
ISSN0028-0836
DOI
StatusUdgivet - 11 maj 2017

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