Antigen presentation by keratinocytes directs autoimmune skin disease

doi:10.1073/pnas.0437899100

Antigen presentation by keratinocytes directs autoimmune skin disease

^*The Scripps Research Institute, La Jolla, CA 92037; and ^§Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104

Communicated by Laurie H. Glimcher, Harvard School of Public Health, Boston, MA (received for review December 4, 2002)

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_β ^b mice expressing MHC class II only on thymic cortical epithelium. CD4⁺ T cells from K14-A_β ^b mice fail to undergo negative selection and thus have significant autoreactivity. The TCR genes from an autoreactive K14-A_β ^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 C57BL/6 mice but not in 2-2-3/K14-A_β ^b mice. Interestingly, a significant number of mice that express both the K14-A_β ^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.

Footnotes

↵ † The first two authors and the last two authors contributed equally to this work.
↵ ‡ Present address: Pharmacia, 4901 Searle Parkway, Skokie, IL 60077.
↵ ¶ Present address: Digital Gene Technologies, 11149 North Torrey Pines Road, La Jolla, CA 92037.
↵ ‖ To whom correspondence should be addressed at: Department of Medicine, University of Pennsylvania, 753 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104. E-mail: tlaufer{at}mail.med.upenn.edu.
Data deposition: The sequences reported in this article have been deposited in the GenBank database (accession nos. AY056584 and AY056585).
Abbreviations:

APC,

antigen-presenting cell;

LN,

lymph node;

TNF-α,

tumor necrosis factor α;

ICAM,

intercellular adhesion molecule;

K14,

keratin 14;

TCR,

T cell antigen receptor;

Tg,

transgenic;

CFSE,

carboxyl fluorescein succinimide ester;

GVHD,

graft-versus-host disease