CD103)-Deficient Mice
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Mucosal T Lymphocyte Numbers Are Selectively Reduced in Integrin αE (CD103)-Deficient Mice This information is current as Michael P. Schön, Anu Arya, Elizabeth A. Murphy, of September 24, 2021. Cassandra M. Adams, Ulrike G. Strauch, William W. Agace, Jan Marsal, John P. Donohue, Helen Her, David R. Beier, Sara Olson, Leo Lefrancois, Michael B. Brenner, Michael J. Grusby and Christina M. Parker J Immunol 1999; 162:6641-6649; ; Downloaded from http://www.jimmunol.org/content/162/11/6641 References This article cites 43 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/162/11/6641.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 by guest on September 24, 2021 • Fast Publication! 4 weeks from acceptance to publication *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 © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Mucosal T Lymphocyte Numbers Are Selectively Reduced in a 1 Integrin E (CD103)-Deficient Mice Michael P. Scho¨n,2* Anu Arya,* Elizabeth A. Murphy,* Cassandra M. Adams,* Ulrike G. Strauch,* William W. Agace,* Jan Marsal,* John P. Donohue,* Helen Her,† David R. Beier,† Sara Olson,§ Leo Lefrancois,§ Michael B. Brenner,* Michael J. Grusby,*‡ and Christina M. Parker3* a b The mucosal lymphocyte integrin E(CD103) 7 is thought to be important for intraepithelial lymphocyte (IEL) localization or a a function. We cloned the murine integrin gene encoding E, localized it to chromosome 11, and generated integrin E-deficient a 2/2 a b mice. In E mice, intestinal and vaginal IEL numbers were reduced, consistent with the known binding of E 7 to E-cadherin expressed on epithelial cells. However, it was surprising that lamina propria T lymphocyte numbers were diminished, as E- Downloaded from cadherin is not expressed in the lamina propria. In contrast, peribronchial, intrapulmonary, Peyer’s patch, and splenic T lym- a a b phocyte numbers were not reduced in E-deficient mice. Thus, E 7 was important for generating or maintaining the gut and vaginal T lymphocytes located diffusely within the epithelium or lamina propria but not for generating the gut-associated orga- a nized lymphoid tissues. Finally, the impact of E deficiency upon intestinal IEL numbers was greater at 3–4 wk of life than in younger animals, and affected the TCR ab1 CD81 T cells more than the gd T cells or the TCR ab1 CD41CD82 population. a b ab1 1 These findings suggest that E 7 is involved in the expansion/recruitment of TCR CD8 IEL following microbial coloni- http://www.jimmunol.org/ a a b a b zation. Integrin E-deficient mice will provide an important tool for studying the role of E 7 and of E 7-expressing mucosal T lymphocytes in vivo. The Journal of Immunology, 1999, 162: 6641–6649. ucosal T lymphocytes appear to be functionally dis- mune surveillance and immune responses to mucosal pathogens tinct from those in peripheral blood. Indeed, intestinal under normal conditions. In addition, intestinal T lymphocytes M intraepithelial lymphocytes (IEL)4 have been found to have been implicated in the pathogenesis of inflammatory bowel differ from PBL in their Ag-recognition specificity (1–3), acces- diseases, based upon the development of intestinal inflammation in sory costimulatory molecule expression (4), TCR ab and gd type, animals with defects in T lymphocyte regulation (7). Thus, it will and thymus-dependent vs -independent T cell development (re- be important to understand the mechanisms whereby mucosal lym- by guest on September 24, 2021 viewed in Ref. 5). There are estimated to be as many T lympho- phocytes selectively localize and function. cytes in the intestinal immune system as in the spleen (6). Fur- Following primary stimulation in organized lymphoid tissues, thermore, many infectious agents invade via mucosal epithelia, such as mesenteric lymph nodes and Peyer’s patches, some acti- emphasizing the importance of mucosal T lymphocytes for im- vated intestine-derived lymphocytes recirculate and then preferen- tially return to the intestinal tract. The selective expression of che- *Division of Rheumatology, Immunology, and Allergy, and †Division of Genetics, mokine receptors and adhesion molecules are thought to contribute Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; to T cell homing (8). Once in the intestine, lymphocyte subpopu- ‡Department of Immunology and Infectious Disease, Harvard School of Public § lations localize to particular microenvironments. For example, the Health, Boston, MA 02115; and Department of Medicine, University of Connecticut 1 Health Center, Farmington, CT 06030 CD8 T cells are found preferentially within the epithelium, where 1 Received for publication January 12, 1999. Accepted for publication March 17, 1999. they comprise 90% of the resident population, whereas CD4 T The costs of publication of this article were defrayed in part by the payment of page cells predominate in the lamina propria, where they constitute charges. This article must therefore be hereby marked advertisement in accordance more than half of the T lymphocytes (9). Targeted migration along with 18 U.S.C. Section 1734 solely to indicate this fact. chemokine gradients and selective adhesion to extracellular matrix 1 This work was supported by a grant from the Deutsche Forschungsgemeinschaft (to or to cellular counterreceptors may account for the localization and M.P.S. and U.G.S.), grants from the National Institute of Health (NIH) and the Mathers Foundation (to M.J.G., who is a Scholar of the Leukemia Society of Amer- retention of T cell subsets within mucosal microenvironments. ica), National Research Service institutional training grants from the NIH (to C.M.A. One candidate to mediate the selective localization or retention and J.P.D), a fellowship from the Swedish Foundation for International Cooperation a b of intraepithelial T lymphocytes is the integrin E(CD103) 7. This in Research and Higher Education (STINT) (to W.W.A), grants from NIH (to . M.B.B.), grants from NIH, the Crohn’s and Colitis Foundation, the Cancer Research integrin is expressed selectively on 90% of intestinal IEL and on Institute, and a Pilot and Feasibility grant from the Center for the Study of Inflam- 45–50% of lamina propria T lymphocytes (9–11) in both mice and matory Bowel Diseases (to C.M.P), Grant RO1HD29028 from National Institute for humans. It is also found on T lymphocytes in some other mucosal Child Health and Human Development, and Grant ROHG00951 from the National Center for Human Genome Research (to D.R.B.). epithelia, such as the genitourinary epithelium (12), on ;40% of 2 Current address: Department of Dermatology, Heinrich-Heine-University, Mooren- bronchioalveolar lavage T cells obtained from normal humans (13) str. 5, D-40225 Du¨sseldorf, Germany and on some cells of dendritic morphology in rats (14). Further- 3 a b Address correspondence and reprint requests to Dr. Christina M. Parker, Brigham more, E 7 expression can be induced on T lymphocytes and mu- and Women’s Hospital, Smith-552B, 1 Jimmy Fund Way, Boston, MA 02115. E-mail rine mast cells by culture in the presence of TGF-b1 (15), a cy- address: [email protected] tokine produced by intestinal epithelial cells (16) as well as other 4 Abbreviations used in this paper: IEL, intraepithelial lymphocyte; Itgae, integrin a b , a cell types. In contrast, E 7 is expressed on 5% of PBL in hu- gene encoding E; SSCP, single strand conformation polymorphism; SPF, specific pathogen-free; MFI, mean fluorescence intensity. mans (10), on only 15% of splenic T lymphocytes in mice (17), Copyright © 1999 by The American Association of Immunologists 0022-1767/99/$02.00 a 6642 INTEGRIN E-DEFICIENT MICE and has not been found on B lymphocytes, underscoring its selec- matings between chimeric animals and BALB/c mice were intercrossed to 3 tive expression on mucosal T cells. generate F2 (129/Sv BALB/cJ) offspring, which were utilized in these The a b integrin mediates T cell adhesion to epithelial cells experiments except where otherwise indicated. Two independent clones E 7 were used to generate chimeric animals that expressed similar phenotypes. (18) through its binding to E-cadherin (19–21), a member of the All animals were housed under specific pathogen-free (SPF) conditions. cadherin family of adhesion molecules that is expressed selectively on epithelial cells. Cadherins are characterized by their tissue-spe- Genotyping cific distribution and are known to mediate homophilic adhesion of Genomic DNA was isolated from tail biopsies by proteinase K digestion, cells within tissues (22). In addition, evidence has suggested that followed by phenol extraction. Southern blot analysis was performed using a b 10 mg genomic DNA, Hybond-N (Amersham, Arlington Heights, IL) fil- E 7-dependent adhesion is regulated by inside-out signals, based a b ters and digoxigenin-labeled probes (Nonradioactive DNA labeling