Antigen presentation by keratinocytes directs autoimmune skin disease

Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3386-91. doi: 10.1073/pnas.0437899100. Epub 2003 Mar 10.

Abstract

The antigen-presenting cells that initiate and maintain MHC class II-associated organ-specific autoimmune diseases are poorly defined. We now describe a new T cell antigen receptor (TCR) transgenic (Tg) model of inflammatory skin disease in which keratinocytes activate and are the primary target of autoreactive CD4(+) T cells. We previously generated keratin 14 (K14)-A(beta)b mice expressing MHC class II only on thymic cortical epithelium. CD4(+) T cells from K14-A(beta)b mice fail to undergo negative selection and thus have significant autoreactivity. The TCR genes from an autoreactive K14-A(beta)b CD4 hybridoma were cloned to produce a TCR Tg mouse, 2-2-3. 2-2-3 TCR Tg cells are negatively selected in WT C57BL6 mice but not in 2-2-3K14-A(beta)b mice. Interestingly, a significant number of mice that express both the K14-A(beta)b transgene and the autoreactive 2-2-3 TCR spontaneously develop inflammatory skin disease with mononuclear infiltrates, induction of MHC class II expression on keratinocytes, and T helper 1 cytokines. Disease can be induced by skin inflammation but not solely by activation of T cells. Thus, cutaneous immunopathology can be directed through antigen presentation by tissue-resident keratinocytes to autoreactive TCR Tg CD4(+) cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigen Presentation*
  • Autoimmune Diseases / etiology
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / pathology
  • Cell Differentiation
  • Dermatitis / etiology
  • Dermatitis / immunology*
  • Dermatitis / pathology
  • Genes, T-Cell Receptor
  • Hybridomas / immunology
  • Keratinocytes / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology

Associated data

  • GENBANK/AY056584
  • GENBANK/AY056585