Limited peripheral T cell anergy predisposes to retinal autoimmunity

Teresa Lambe, Janson C. H. Leung, Helen Ferry, Tiphaine Bouriez-Jones, Kimmo Antero Makinen, Tanya L. Crockford, Hui R. Jiang, John M. Nickerson, Leena Peltonen, John V. Forrester, Richard J. Cornall

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Autoimmune uveoretinitis accounts for at least 10% of worldwide blindness, yet it is unclear why tolerance to retinal Ags is so fragile and, particularly, to what extent this might be due to defects in peripheral tolerance. To address this issue, we generated double-transgenic mice expressing hen egg lysozyme, under the retinal interphotoreceptor retinoid-binding promoter, and a hen egg lysozyme-specific CD4(+) TCR transgene. In this manner, we have tracked autoreactive CD4(+) T cells from their development in the thymus to their involvement in uveoretinitis and compared tolerogenic mechanisms induced in a variety of organs to the same self-Ag. Our findings show that central tolerance to retinal and pancreatic Ags is qualitatively similar and equally dependent on the transcriptional regulator protein AIRE. However, the lack of Ag presentation in the eye-draining lymph nodes results in a failure to induce high levels of T cell anergy. Under these circumstances, despite considerable central deletion, low levels of retinal-specific autoreactive CD4(+) T cells can induce severe autoimmune disease. The relative lack of anergy induction by retinal Ags, in contrast to the same Ag in other organs, helps to explain the unique susceptibility of the eye to spontaneous and experimentally induced autoimmune disease.

Original languageEnglish
Pages (from-to)4276-4283
Number of pages8
JournalThe Journal of Immunology
Volume178
Issue number7
Publication statusPublished - 1 Apr 2007

Keywords

  • resting dendritic cells
  • reactive lymphocytes-b
  • transgenic mice
  • in-vivo
  • antigen presentation
  • thymic expression
  • self-tolerance
  • steady-state
  • negative selection
  • cross-presentation

Cite this

Lambe, T., Leung, J. C. H., Ferry, H., Bouriez-Jones, T., Makinen, K. A., Crockford, T. L., ... Cornall, R. J. (2007). Limited peripheral T cell anergy predisposes to retinal autoimmunity. The Journal of Immunology, 178(7), 4276-4283.

Limited peripheral T cell anergy predisposes to retinal autoimmunity. / Lambe, Teresa; Leung, Janson C. H.; Ferry, Helen; Bouriez-Jones, Tiphaine; Makinen, Kimmo Antero; Crockford, Tanya L.; Jiang, Hui R.; Nickerson, John M.; Peltonen, Leena; Forrester, John V.; Cornall, Richard J.

In: The Journal of Immunology, Vol. 178, No. 7, 01.04.2007, p. 4276-4283.

Research output: Contribution to journalArticle

Lambe, T, Leung, JCH, Ferry, H, Bouriez-Jones, T, Makinen, KA, Crockford, TL, Jiang, HR, Nickerson, JM, Peltonen, L, Forrester, JV & Cornall, RJ 2007, 'Limited peripheral T cell anergy predisposes to retinal autoimmunity' The Journal of Immunology, vol. 178, no. 7, pp. 4276-4283.
Lambe T, Leung JCH, Ferry H, Bouriez-Jones T, Makinen KA, Crockford TL et al. Limited peripheral T cell anergy predisposes to retinal autoimmunity. The Journal of Immunology. 2007 Apr 1;178(7):4276-4283.
Lambe, Teresa ; Leung, Janson C. H. ; Ferry, Helen ; Bouriez-Jones, Tiphaine ; Makinen, Kimmo Antero ; Crockford, Tanya L. ; Jiang, Hui R. ; Nickerson, John M. ; Peltonen, Leena ; Forrester, John V. ; Cornall, Richard J. / Limited peripheral T cell anergy predisposes to retinal autoimmunity. In: The Journal of Immunology. 2007 ; Vol. 178, No. 7. pp. 4276-4283.
@article{fb1674af937a44e1a2f12e2bf31dd247,
title = "Limited peripheral T cell anergy predisposes to retinal autoimmunity",
abstract = "Autoimmune uveoretinitis accounts for at least 10{\%} of worldwide blindness, yet it is unclear why tolerance to retinal Ags is so fragile and, particularly, to what extent this might be due to defects in peripheral tolerance. To address this issue, we generated double-transgenic mice expressing hen egg lysozyme, under the retinal interphotoreceptor retinoid-binding promoter, and a hen egg lysozyme-specific CD4(+) TCR transgene. In this manner, we have tracked autoreactive CD4(+) T cells from their development in the thymus to their involvement in uveoretinitis and compared tolerogenic mechanisms induced in a variety of organs to the same self-Ag. Our findings show that central tolerance to retinal and pancreatic Ags is qualitatively similar and equally dependent on the transcriptional regulator protein AIRE. However, the lack of Ag presentation in the eye-draining lymph nodes results in a failure to induce high levels of T cell anergy. Under these circumstances, despite considerable central deletion, low levels of retinal-specific autoreactive CD4(+) T cells can induce severe autoimmune disease. The relative lack of anergy induction by retinal Ags, in contrast to the same Ag in other organs, helps to explain the unique susceptibility of the eye to spontaneous and experimentally induced autoimmune disease.",
keywords = "resting dendritic cells, reactive lymphocytes-b, transgenic mice, in-vivo, antigen presentation, thymic expression, self-tolerance, steady-state, negative selection, cross-presentation",
author = "Teresa Lambe and Leung, {Janson C. H.} and Helen Ferry and Tiphaine Bouriez-Jones and Makinen, {Kimmo Antero} and Crockford, {Tanya L.} and Jiang, {Hui R.} and Nickerson, {John M.} and Leena Peltonen and Forrester, {John V.} and Cornall, {Richard J.}",
year = "2007",
month = "4",
day = "1",
language = "English",
volume = "178",
pages = "4276--4283",
journal = "The Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "7",

}

TY - JOUR

T1 - Limited peripheral T cell anergy predisposes to retinal autoimmunity

AU - Lambe, Teresa

AU - Leung, Janson C. H.

AU - Ferry, Helen

AU - Bouriez-Jones, Tiphaine

AU - Makinen, Kimmo Antero

AU - Crockford, Tanya L.

AU - Jiang, Hui R.

AU - Nickerson, John M.

AU - Peltonen, Leena

AU - Forrester, John V.

AU - Cornall, Richard J.

PY - 2007/4/1

Y1 - 2007/4/1

N2 - Autoimmune uveoretinitis accounts for at least 10% of worldwide blindness, yet it is unclear why tolerance to retinal Ags is so fragile and, particularly, to what extent this might be due to defects in peripheral tolerance. To address this issue, we generated double-transgenic mice expressing hen egg lysozyme, under the retinal interphotoreceptor retinoid-binding promoter, and a hen egg lysozyme-specific CD4(+) TCR transgene. In this manner, we have tracked autoreactive CD4(+) T cells from their development in the thymus to their involvement in uveoretinitis and compared tolerogenic mechanisms induced in a variety of organs to the same self-Ag. Our findings show that central tolerance to retinal and pancreatic Ags is qualitatively similar and equally dependent on the transcriptional regulator protein AIRE. However, the lack of Ag presentation in the eye-draining lymph nodes results in a failure to induce high levels of T cell anergy. Under these circumstances, despite considerable central deletion, low levels of retinal-specific autoreactive CD4(+) T cells can induce severe autoimmune disease. The relative lack of anergy induction by retinal Ags, in contrast to the same Ag in other organs, helps to explain the unique susceptibility of the eye to spontaneous and experimentally induced autoimmune disease.

AB - Autoimmune uveoretinitis accounts for at least 10% of worldwide blindness, yet it is unclear why tolerance to retinal Ags is so fragile and, particularly, to what extent this might be due to defects in peripheral tolerance. To address this issue, we generated double-transgenic mice expressing hen egg lysozyme, under the retinal interphotoreceptor retinoid-binding promoter, and a hen egg lysozyme-specific CD4(+) TCR transgene. In this manner, we have tracked autoreactive CD4(+) T cells from their development in the thymus to their involvement in uveoretinitis and compared tolerogenic mechanisms induced in a variety of organs to the same self-Ag. Our findings show that central tolerance to retinal and pancreatic Ags is qualitatively similar and equally dependent on the transcriptional regulator protein AIRE. However, the lack of Ag presentation in the eye-draining lymph nodes results in a failure to induce high levels of T cell anergy. Under these circumstances, despite considerable central deletion, low levels of retinal-specific autoreactive CD4(+) T cells can induce severe autoimmune disease. The relative lack of anergy induction by retinal Ags, in contrast to the same Ag in other organs, helps to explain the unique susceptibility of the eye to spontaneous and experimentally induced autoimmune disease.

KW - resting dendritic cells

KW - reactive lymphocytes-b

KW - transgenic mice

KW - in-vivo

KW - antigen presentation

KW - thymic expression

KW - self-tolerance

KW - steady-state

KW - negative selection

KW - cross-presentation

M3 - Article

VL - 178

SP - 4276

EP - 4283

JO - The Journal of Immunology

JF - The Journal of Immunology

SN - 0022-1767

IS - 7

ER -