HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Reynoso, E. D. Articles by Turley, S. J. Search for Related Content PubMed PubMed Citation Articles by Reynoso, E. D. Articles by Turley, S. J.

Intestinal Tolerance Is Converted to Autoimmune Enteritis upon PD-1 Ligand Blockade¹

Erika D. Reynoso^*,, Kutlu G. Elpek, Loise Francisco^,, Roderick Bronson, Angélique Bellemare-Pelletier, Arlene H. Sharpe, Gordon J. Freeman^¶ and Shannon J. Turley^2,,

^* Division of Medical Sciences, Department of Pathology, Harvard Medical School, Brigham and Women’s Hospital, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, ^¶ Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02115

The B7 family member programmed death-1 ligand (PD-L1) has been shown to play an inhibitory role in the regulation of T cell responses in several organs. However, the role of PD-L1 in regulating tolerance to self-Ags of the small intestine has not been previously addressed. In this study, we investigated the role of PD-L1 in CD8⁺ T cell tolerance to an intestinal epithelium-specific Ag using the iFABP-tOVA transgenic mouse model, in which OVA is expressed as a self-Ag throughout the small intestine. Using adoptive transfer of naive OVA-specific CD8⁺ T cells, we show that loss of PD-1:PD-L1 signaling, by either Ab-mediated PD-L1 blockade or transfer of PD-1^–/– T cells, leads to considerable expansion of OVA-specific CD8⁺ T cells and their differentiation into effector cells capable of producing proinflammatory cytokines. A fatal CD8⁺ T cell-mediated inflammatory response develops rapidly against the small bowel causing destruction of the epithelial barrier, severe blunting of intestinal villi, and recruitment and activation of myeloid cells. This response is highly specific because immune destruction selectively targets the small intestine but not other organs. Collectively, these results indicate that loss of the PD-1:PD-L1 inhibitory pathway breaks CD8⁺ T cell tolerance to intestinal self-Ag, thus leading to severe enteric autoimmunity.

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 with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a grant from the Claudia Adams Barr Program for Innovative Cancer Research (to S.J.T.), the Baruj Benacerraf Fellowship in Immunology (to K.G.E.), and National Institutes of Health Grants R01 DK074500 (to S.J.T.) and AI56299 (to A.H.S. and G.J.F.).

² Address correspondence and reprint requests to Dr. Shannon J. Turley, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, Room D1440a, Boston, MA 02115. E-mail address: shannon_turley{at}dfci.harvard.edu

³ Abbreviations used in this paper: PD-1, programmed cell death-1; IEC, intestinal epithelial cell; IEL, intestinal epithelial lymphocyte; DC, dendritic cell; iFABP, intestinal fatty acid binding protein; UEA, Ulex europaeus agglutinin; LNSC, lymph node stromal cell.

⁴ The online version of this article contains supplemental material.

This article has been cited by other articles:

				E. D. Reynoso and S. J. Turley Unconventional antigen-presenting cells in the induction of peripheral CD8+ T cell tolerance J. Leukoc. Biol., October 1, 2009; 86(4): 795 - 801. [Abstract] [Full Text] [PDF]