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 Anthony Power, Stephen G. Holt, P. Toby Coates, Jon W. Gregersen, Anthony W. Purcell & 5 others Stephen R. Holdsworth, Nicole L. La Gruta, Hugh H. Reid, Jamie Rossjohn, A. Richard Kitching

Research output: Contribution to journalArticleResearchpeer-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.

Original languageEnglish
Pages (from-to)243-247
Number of pages5
JournalNature
Volume545
Issue number7653
DOIs
Publication statusPublished - 11 May 2017

Keywords

  • autoimmunity
  • kidney

Cite this

Ooi, Joshua D. ; Petersen, Jan ; Tan, Yu H. ; Huynh, Megan ; Willett, Zoe J. ; Ramarathinam, Sri H. ; Eggenhuizen, Peter J. ; Loh, Khai L. ; Watson, Katherine A. ; Gan, Poh Y. ; Alikhan, Maliha A. ; Dudek, Nadine L. ; Handel, Andreas ; Hudson, Billy G ; Fugger, Lars ; Power, David Anthony ; Holt, Stephen G. ; Coates, P. Toby ; Gregersen, Jon W. ; Purcell, Anthony W. ; Holdsworth, Stephen R. ; La Gruta, Nicole L. ; Reid, Hugh H. ; Rossjohn, Jamie ; Kitching, A. Richard. / Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. In: Nature. 2017 ; Vol. 545, No. 7653. pp. 243-247.
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title = "Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells",
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.",
keywords = "autoimmunity, kidney",
author = "Ooi, {Joshua D.} and Jan Petersen and Tan, {Yu H.} and Megan Huynh and Willett, {Zoe J.} and Ramarathinam, {Sri H.} and Eggenhuizen, {Peter J.} and Loh, {Khai L.} and Watson, {Katherine A.} and Gan, {Poh Y.} and Alikhan, {Maliha A.} and Dudek, {Nadine L.} and Andreas Handel and Hudson, {Billy G} and Lars Fugger and Power, {David Anthony} and Holt, {Stephen G.} and Coates, {P. Toby} and Gregersen, {Jon W.} and Purcell, {Anthony W.} and Holdsworth, {Stephen R.} and {La Gruta}, {Nicole L.} and Reid, {Hugh H.} and Jamie Rossjohn and Kitching, {A. Richard}",
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Ooi, JD, Petersen, J, Tan, YH, Huynh, M, Willett, ZJ, Ramarathinam, SH, Eggenhuizen, PJ, Loh, KL, Watson, KA, Gan, PY, Alikhan, MA, Dudek, NL, Handel, A, Hudson, BG, Fugger, L, Power, DA, Holt, SG, Coates, PT, Gregersen, JW, Purcell, AW, Holdsworth, SR, La Gruta, NL, Reid, HH, Rossjohn, J & Kitching, AR 2017, 'Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells' Nature, vol. 545, no. 7653, pp. 243-247. https://doi.org/10.1038/nature22329

Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. / Ooi, Joshua D.; Petersen, Jan; Tan, Yu H.; Huynh, Megan; Willett, Zoe J.; Ramarathinam, Sri H.; Eggenhuizen, Peter J.; Loh, Khai L.; Watson, Katherine A.; Gan, Poh Y.; Alikhan, Maliha A.; Dudek, Nadine L.; Handel, Andreas; Hudson, Billy G; Fugger, Lars; Power, David Anthony; Holt, Stephen G.; Coates, P. Toby; Gregersen, Jon W.; Purcell, Anthony W.; Holdsworth, Stephen R.; La Gruta, Nicole L.; Reid, Hugh H.; Rossjohn, Jamie; Kitching, A. Richard.

In: Nature, Vol. 545, No. 7653, 11.05.2017, p. 243-247.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells

AU - Ooi, Joshua D.

AU - Petersen, Jan

AU - Tan, Yu H.

AU - Huynh, Megan

AU - Willett, Zoe J.

AU - Ramarathinam, Sri H.

AU - Eggenhuizen, Peter J.

AU - Loh, Khai L.

AU - Watson, Katherine A.

AU - Gan, Poh Y.

AU - Alikhan, Maliha A.

AU - Dudek, Nadine L.

AU - Handel, Andreas

AU - Hudson, Billy G

AU - Fugger, Lars

AU - Power, David Anthony

AU - Holt, Stephen G.

AU - Coates, P. Toby

AU - Gregersen, Jon W.

AU - Purcell, Anthony W.

AU - Holdsworth, Stephen R.

AU - La Gruta, Nicole L.

AU - Reid, Hugh H.

AU - Rossjohn, Jamie

AU - Kitching, A. Richard

PY - 2017/5/11

Y1 - 2017/5/11

N2 - 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.

AB - 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.

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