5V4M

Structure of HLA-DR15 with bound alpha3(135-145) peptide

Summary for 5V4M

• Entry DOI: 10.2210/pdb5v4m/pdb
• Descriptor: HLA-DRA1, alpha3(135-145)-HLA-DRB1*15:01, alpha-L-fucopyranose-(1-3)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: hla-dr, immune complex, antigen presenation, immune system
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane; Single-pass type I membrane protein: P01903 P01911
• Total number of polymer chains: 8
• Total formula weight: 189016.73

Authors

Petersen, J.,Rossjohn, J. (deposition date: 2017-03-10, release date: 2017-05-03, Last modification date: 2024-10-09)

Primary citation

Ooi, J.D.,Petersen, J.,Tan, Y.H.,Huynh, M.,Willett, Z.J.,Ramarathinam, S.H.,Eggenhuizen, P.J.,Loh, K.L.,Watson, K.A.,Gan, P.Y.,Alikhan, M.A.,Dudek, N.L.,Handel, A.,Hudson, B.G.,Fugger, L.,Power, D.A.,Holt, S.G.,Coates, P.T.,Gregersen, J.W.,Purcell, A.W.,Holdsworth, S.R.,La Gruta, N.L.,Reid, H.H.,Rossjohn, J.,Kitching, A.R.
Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells.
Nature, 545:243-247, 2017

PubMed 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 self-epitope derived from the α3 chain of type IV collagen (α3). 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 α3-specific T cells expand in patients with Goodpasture disease and, in α3-immunized HLA-DR15 transgenic mice, α3-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 α3 epitope in different binding registers. HLA-DR15-α3 tetramer T cells in HLA-DR15 transgenic mice exhibit a conventional T-cell phenotype (T) that secretes pro-inflammatory cytokines. In contrast, HLA-DR1-α3 tetramer T cells in HLA-DR1 and HLA-DR15/DR1 transgenic mice are predominantly CD4Foxp3 regulatory T cells (T cells) expressing tolerogenic cytokines. HLA-DR1-induced T cells confer resistance to disease in HLA-DR15/DR1 transgenic mice. HLA-DR15 and HLA-DR1 healthy human donors display altered α3-specific T-cell antigen receptor usage, HLA-DR15-α3 tetramer Foxp3 T and HLA-DR1-α3 tetramer Foxp3CD25CD127 T dominant phenotypes. Moreover, patients with Goodpasture disease display a clonally expanded α3-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 T cells that leads to protection or causation of autoimmunity.

PubMed: 28467828
DOI: 10.1038/nature22329

Experimental method

X-RAY DIFFRACTION (2.1 Å)