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A CD8⁺/CD103^high T Cell Subset Regulates TNF-Mediated Chronic Murine Ileitis¹

Johnson Ho^*, Courtney C. Kurtz^*, Makoto Naganuma^*, Peter B. Ernst^*, Fabio Cominelli^* and Jesús Rivera-Nieves^2,*,

^* Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, VA 22908; and Mucosal Inflammation Program, Division of Gastroenterology, University of Colorado Health Sciences Center, Denver, CO 80206

Recruitment of lymphocytes to sites of inflammation requires the sequential engagement of adhesion molecules and chemokine receptors. Of these, the lectin-like molecule CD44 has been particularly implicated in inflammatory trafficking. Using a TNF-driven model of chronic ileitis (i.e., B6.129P-Tnf^ARE mice) that recapitulates many features of Crohn’s disease, we demonstrate dynamic changes in the expression and functional state of CD44 on CD8⁺ T cells. These cells coexpress CD44 and L-selectin, giving them a surface phenotype similar to that of central memory T cells. Yet functionally they exhibit the phenotype of effector T cells, because they produce IFN-. Unexpectedly, depletion of the CD8⁺ population had no effect on the severity of ileitis. Further analyses showed a second CD8⁺ population that lacked CD44, but expressed CD103, produced TGF-β, inhibited the proliferation of CD4⁺ in vitro, and attenuated adoptively transferred ileitis in vivo, most likely counteracting the proinflammatory role of the CD44^high subset. Collectively, these data suggest that the presence or absence of CD44 and CD103 on the CD8⁺ lymphocyte surface defines functionally distinct subsets of CD8⁺ T cells in vivo. These inflammation-driven populations exert distinct roles during the development of chronic ileitis, and influence the balance of effector and regulatory functions in the chronically inflamed small intestine.

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 by U.S. Public Health Service/National Institutes of Health Grants KO8DK067254 and RO3DK073280 (to J.R.-N.), R21AI069880 (to P.B.E.), and R37DK42191-16 (to F.C.), and by the Morphology and Immunology Cores of the University of Virginia Silvio Conte Digestive Health Research Center (DK56703).

² Address correspondence and reprint requests to Dr. Jesús Rivera-Nieves, Mucosal Inflammation Program, Division of Gastroenterology, University of Colorado Health Sciences Center, BRB, Room 742A, 4200 East 9th Avenue, Denver, CO 80206. E-mail address: jesus.rivera-nieves{at}uchsc.edu

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; ARE, AU-rich region; CD, Crohn’s disease; FSC, forward scatter; MFI, mean fluorescence intensity; MLN, mesenteric lymph node; SSC, side scatter; T_reg, regulatory T cell; WT, wild type.