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Mouse TCR⁺CD8 Intraepithelial Lymphocytes Express Genes That Down-Regulate Their Antigen Reactivity and Suppress Immune Responses^1,2

Timothy L. Denning^3,*, Steve Granger, Daniel Mucida^*, Ryan Graddy^*, Georges Leclercq, Weiguo Zhang, Karen Honey^¶, Jeffrey P. Rasmussen^¶, Hilde Cheroutre^*, Alexander Y. Rudensky^¶ and Mitchell Kronenberg^3,*

^* Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, and Gemini Science. La Jolla, CA 92037; Department of Clinical Chemistry, Microbiology, and Immunology, University of Ghent, University Hospital, Ghent, Belgium; Department of Immunology, Duke University Medical Center, Durham, NC 27710; and ^¶ Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195

Mouse small intestine intraepithelial lymphocytes (IEL) that express TCR and CD8 homodimers are an enigmatic T cell subset, as their specificity and in vivo function remain to be defined. To gain insight into the nature of these cells, we performed global gene expression profiling using microarray analysis combined with real-time quantitative PCR and flow cytometry. Using these methods, TCR⁺CD8 IEL were compared with their TCR⁺CD8⁺ and TCR⁺ counterparts. Interestingly, TCR⁺CD8 IEL were found to preferentially express genes that would be expected to down-modulate their reactivity. They have a unique expression pattern of members of the Ly49 family of NK receptors and tend to express inhibitory receptors, along with some activating receptors. The signaling machinery of both TCR⁺CD8 and TCR⁺ IEL is constructed differently than other IEL and peripheral T cells, as evidenced by their low-level expression of the linker for activation of T cells and high expression of the non-T cell activation linker, which suppresses T cell activation. The TCR⁺CD8 IEL subset also has increased expression of genes that could be involved in immune regulation, including TGF-₃ and lymphocyte activation gene-3. Collectively, these data underscore the fact that, while TCR⁺CD8 IEL resemble TCR⁺ IEL, they are a unique population of cells with regulated Ag reactivity that could have regulatory function.

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 is supported by National Institutes of Health Grants P01 DK46763 and R01 AI 65016 (to M.K). T.L.D. is a recipient of a Jeane B. Kempner Scholarship from the University of Texas Medical Branch at Galveston.

² This is Publication Number 781 from the La Jolla Institute for Allergy and Immunology.

³ Address correspondence and reprint requests to Dr. Mitchell Kronenberg, Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037; E-mail address: mitch{at}liai.org or Dr. Timothy L. Denning, Emory Vaccine Center, Atlanta, GA 30329; E-mail address: tdennin{at}emory.edu

⁴ Abbreviations used in this paper: IEL, intestine intraepithelial lymphocyte; DAP12, DNAX-activating protein of 12 kDa; DC, dendritic cell; EAT2, Ewing’s sarcoma/FLI1-activated transcript 2; fgl2, fibrinogen-like protein-2; LAB, linker for activation of B cell; LAG-3, lymphocyte activation gene-3; LAT, linker for activation of T cell; NTAL, non-T cell activation linker; SAP, signaling lymphocytic activation molecule-associated protein; V14i, invariant V14.

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