Under the Human Keratin 14 Promoter Expressed Autoimmune Disease to an Antigen a Spontaneous CD8 T Cell-Dependent

A Spontaneous CD8 T Cell-Dependent Autoimmune Disease to an Antigen Expressed Under the Human Keratin 14 Promoter This information is current as Maureen A. McGargill, Dita Mayerova, Heather E. Stefanski, of September 26, 2021. Brent Koehn, Evan A. Parke, Stephen C. Jameson, Angela Panoskaltsis-Mortari and Kristin A. Hogquist J Immunol 2002; 169:2141-2147; ; doi: 10.4049/jimmunol.169.4.2141 http://www.jimmunol.org/content/169/4/2141 Downloaded from References This article cites 44 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/169/4/2141.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 26, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology A Spontaneous CD8 T Cell-Dependent Autoimmune Disease to an Antigen Expressed Under the Human Keratin 14 Promoter1 Maureen A. McGargill,*‡ Dita Mayerova,*‡ Heather E. Stefanski,*‡ Brent Koehn,*‡ Evan A. Parke,*‡ Stephen C. Jameson,*‡ Angela Panoskaltsis-Mortari,†‡ and Kristin A. Hogquist2*‡ Using a previously described human keratin 14 (K14) promoter, we created mice expressing a peptide Ag (OVAp) in epithelial cells of the skin, tongue, esophagus, and thymus. Double transgenic mice that also express a TCR specific for this Ag (OT-I) showed evidence for Ag-driven receptor editing in the thymus. Surprisingly, such mice exhibited a severe autoimmune disease. In this work we describe the features of this disease and demonstrate that it is dependent on CD8 T cells. Consistent with the Ag expression pattern dictated by the human K14 promoter, an inflammatory infiltrate was observed in skin and esophagus and Downloaded from around bile ducts of the liver. We also observed a high level of TNF-␣ in the serum. Given that Ag expression in the thymus induced development of T cells with dual TCR reactivity, and that dual-reactive cells have been suggested to have autoimmune potential, we tested whether they were a causal factor in the disease observed here. We found that OT-I/K14-OVAp animals on a recombinase-activating gene-deficient background still suffered from disease. In addition, OT-I animals expressing OVA broadly in all tissues under a different promoter did not experience disease, despite having a similar number of dual-specific T cells. Thus, in this model it would appear that dual-reactive T cells do not underlie autoimmune pathology. Finally, we extended these http://www.jimmunol.org/ observations to a second transgenic system involving 2C TCR-transgenic animals expressing the SIY peptide Ag with the hK14 promoter. We discuss the potential relationship between autoimmunity and self-Ags that are expressed in stratified epithelium. The Journal of Immunology, 2002, 169: 2141–2147. olerance reflects the ability of the immune system to dis- ceptor, and CD5, to reduce their sensitivity and avoid deletion tinguish between healthy and infected tissue. For T cells, (5–7). T cells can also avoid deletion in the thymus by secondary T an important mechanism to establish tolerance occurs TCR gene rearrangement, which occurs during allelic inclusion (8) during development in the thymus. In this study, developing T and receptor editing (9). When the secondary gene rearrangement cells that express a self-Ag-reactive TCR are induced to die via event occurs on the same allele as the primary, the primary TCR by guest on September 26, 2021 apoptosis, thereby eliminating dangerous T cell clones before they chain is replaced. When it occurs on the alternate allele it results complete development (1). At least two mechanisms exist to en- in the synthesis of two TCR chains. In this later case, the second sure that a wide variety of self-Ags are presented to T cells in the chain can compete with the first during pairing and assembly and thymus. First, bone marrow-derived APCs can cross-present ex- thereby alter the T cell reactivity. T cells with two productive ogenous Ags that are not synthesized within thymic APC (2). Sec- rearrangements of the same TCR chain are referred to as dual- ond, medullary epithelial cells are apparently specialized for pro- reactive, even though one specificity may predominate. miscuous expression of otherwise tissue-specific gene products Although receptor editing is viewed as a tolerance mechanism, (3). Peptides from these are presented to developing T cells and dual-reactive T cells have been shown to have autoimmune poten- induce immune tolerance. Nonetheless, in both humans and mice, tial. In one model, dual-reactive CD4ϩ T cells were observed in autoreactive T cells escape deletion in the thymus and circulate mice that expressed a TCR transgene specific for an influenza through the body. Their autoaggressive potential after maturation hemagglutinin along with the hemagglutinin Ag (10). The Ag was in the thymus is further controlled by peripheral tolerance mech- expressed in hemopoietic cells with the Ig ␬ promoter and in the anisms (4). pancreas with the rat insulin promoter. Although the majority of There are numerous ways in which T cells with autoreactive hemagglutinin-specific T cells were deleted in the thymus, CD4ϩ receptors could escape clonal deletion in the thymus. T cells can T cells that expressed the transgenic TCR were detected in the modulate the level of surface molecules, such as the TCR, core- peripheral lymphoid organs and the pancreas. While these T cells were anergic when tested in vitro, 25% of the mice developed mild diabetes. Adoptive transfer experiments demonstrated that it was † ‡ Departments of *Laboratory Medicine and Pathology and Pediatrics and Center for the CD4ϩ T cells that expressed low levels of the transgenic Immunology, University of Minnesota, Minneapolis, MN 55455 ␣-chain along with an endogenously rearranged ␣-chain that in- Received for publication March 4, 2002. Accepted for publication June 11, 2002. duced diabetes. In another system, constitutive expression of two The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance transgenic TCRs allowed T cells to escape deletion in the thymus with 18 U.S.C. Section 1734 solely to indicate this fact. (11). These cells were tolerant in the periphery but could be acti- 1 This work was funded by National Institutes of Health Grants PO1 AI 35296 and vated in vitro through either TCR. These experiments suggest that RO1 AI 39560 and the University of Minnesota Graduate School. dual-reactive T cells may play a dominant role in induction of 2 Address correspondence and reprint requests to Dr. Kristin A. Hogquist, De- spontaneous autoimmune disease (12). partment of Laboratory Medicine and Pathology, University of Minnesota, Box 334, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail address: We previously reported a TCR-transgenic strain where expres- [email protected] sion of self-Ag in the thymus resulted in receptor editing. These Copyright © 2002 by The American Association of Immunologists, Inc. 0022-1767/02/$02.00 2142 SPONTANEOUS CD8 T CELL AUTOIMMUNE DISEASE mice expressed the OT-I TCR, specific for a peptide epitope from injected i.p. every fourth day from birth to wk 1 (50 ␮g), from wk 1 to wk OVA in the context of the Kb MHC molecule. When the OVA 3 (100 ␮g), and from wk 3 to wk 6 (150 ␮g). All mice were weighed and peptide Ag was expressed in the thymus under the human keratin 14 monitored for signs of disease every other day. Mice remaining at the end 3 ϩ ϩ of wk 6 were sacrificed. Serum was taken for analysis as described above. (K14) promoter, only a modest reduction in thymic CD4 CD8 Lymph node and spleen were analyzed for T cell depletion by flow cy- double positive cells was observed. TCR␣ gene rearrangement was tometry. Depletion Ͼ95% was observed in all animals. highly elevated in these precursors, and the predominant T cell population that matured expressed both the transgenic receptor and Results an endogenous TCR␣ chain. Surprisingly, OT-I/K14-OVAp ani- We studied TCR-transgenic mice that expressed the antigenic pep- mals exhibited a lethal disease between 2 and 6 wk of age. In this tide ligand in the thymus, skin, and esophagus (9). The transgenic report we describe the features of this disease and provide evi- TCR was the OT-I TCR that recognizes a peptide from chicken dence that it is a CD8-mediated autoimmune disease with signif- OVA (OVAp) in the context of the MHC class I molecule, Kb. The icant manifestation in the skin. Because of the large dual-reactive antigenic peptide, OVAp, was also expressed as a transgene under T cell population in these mice, and because such cells have pre- the control of a human keratinocyte-specific promoter, K14. This viously been reported to have autoimmune potential, we tested the promoter directs expression in epithelial cells of the thymus as hypothesis that dual-reactive T cells play a dominant role in spon- well as the skin, esophagus, and tongue (17). We previously re- taneous disease induction in this model.

Load more