Cells T Lymphocytes Is Independent of NK T Involvement of CD1 in Peripheral Deletion Of

Involvement of CD1 in Peripheral Deletion of T Lymphocytes Is Independent of NK T Cells Tao Dao, Mark Exley, Wajahat Z. Mehal, Syed Muhammad Ali Tahir, Scott Snapper, Masaru Taniguchi, Steven P. Balk This information is current as and I. Nicholas Crispe of September 28, 2021. J Immunol 2001; 166:3090-3097; ; doi: 10.4049/jimmunol.166.5.3090 http://www.jimmunol.org/content/166/5/3090 Downloaded from References This article cites 53 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/166/5/3090.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 28, 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 © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Involvement of CD1 in Peripheral Deletion of T Lymphocytes Is Independent of NK T Cells1 Tao Dao,* Mark Exley,† Wajahat Z. Mehal,* Syed Muhammad Ali Tahir,† Scott Snapper,‡ Masaru Taniguchi,§ Steven P. Balk,† and I. Nicholas Crispe2* During peripheral T cell deletion, lymphocytes accumulate in nonlymphoid organs including the liver, a tissue that expresses the nonclassical, MHC-like molecule, CD1. Injection of anti-CD3 Ab results in T cell activation, which in normal mice is followed by peripheral T cell deletion. However, in CD1-deficient mice, the deletion of the activated T cells from the lymph nodes was impaired. -This defect in peripheral T cell deletion was accompanied by attenuated accumulation of CD8؉ T cells in the liver. In tetra parental bone marrow chimeras, expression of CD1 on the T cells themselves was not required for T cell deletion, suggesting a role for CD1 on other cells with which the T cells interact. We tested whether this role was dependent on the Ag receptor-invariant, CD1-reactive subset of NK T cells using two other mutant mouse lines that lack most NK T cells, due to deletion of the genes Downloaded from ␤ ␣ encoding either 2-microglobulin or the TCR element J 281. However, these mice had no abnormality of peripheral T cell deletion. These findings indicate a novel role for CD1 in T cell deletion, and show that CD1 functions in this process through mechanisms that does not involve the major, TCR-invariant set of NK T cells. The Journal of Immunology, 2001, 166: 3090–3097. he activation of T cells by nonphysiological stimuli, such (reviewed in Refs. 14 and 15)). This latter population contains a as superantigens and Abs against the TCR, results in ac- subset of cells that express a distinctive TCR␣␤, in which the http://www.jimmunol.org/ T tivation-induced cell death and deletion of the T cells TCR␤-chain is of very limited diversity and the TCR␣-chain is from the periphery (1–5). Similarly, injection of specific antigenic essentially monomorphic. These cells depend for their develop- ␤ peptide into TCR-transgenic mice leads to a truncated, abortive ment and function on CD1 molecules, which are 2-microglobu- immune response in which T cell activation is rapidly followed by lin-associated, MHC class I-like molecules encoded outside the peripheral deletion (6, 7). In some experimental models, peripheral gene complex on chromosome 17 (reviewed in Refs. 16–18)). deletion is due to apoptosis of the activated T cells in lymphoid Mice with induced mutations in key recognition molecules tissues (8). In other models, apoptosis is difficult to detect in the make it possible to determine precisely which subsets of CD1- lymphoid tissue, and activated T cells recirculate to specific de- reactive or NK-like T cells are involved in any biological process. by guest on September 28, 2021 struction sites (9–11). Thus, mice lacking the invariant TCR J region, J␣281, specifically Our previous research has identified the liver as a site for the ϩ lack CD1-reactive T cells with this invariant Ag receptor (19–21). accumulation and destruction of CD8 T cells during peripheral Mice deficient in CD1 lack these invariant T cells, and also other deletion, induced in a TCR-transgenic mouse by the injection of ␤ CD1-reactive T cells. Mice deficient in 2-microglobulin display a antigenic peptide (10). Intrahepatic accumulation of apoptotic T similar defect to CD1-deficient mice (22, 23), except that they cells has been reported in several other models of peripheral T cell ␤ contain a small population of 2-microglobulin-independent T deletion, raising the possibility that this is a general site of T cell cells with NK markers, which increases with age (24). All of these death (11–13). The liver is an unusual immunologic environment, cell populations include NK-like T cells, and in this report we use in which a population of T cells similar to the circulating CD4ϩ the generic term NK T cells to embrace all of them. and CD8ϩ T cells coexists with a subset of CD4Ϫ, The intrahepatic population of NK T cells is cytotoxic though CD8Ϫ,B220ϩ,TCR␣␤ϩ cells that contains a high frequency of ap- ϩ both Fas ligand-mediated and perforin-mediated mechanisms. The optotic cells, and with an abundant subset of NK-1.1 T cells cytokine IL-18, which is produced in large amounts by the resident liver macrophages (termed Kupffer cells), can augment the perforin-dependent cytotoxicity of liver NK T cells (25). We postu- *Immunobiology Section, Yale University School of Medicine, New Haven, CT 06510; †Cancer Biology Program, Division of Hematology/Oncology, Beth Israel lated that these cells might be involved in the intrahepatic killing Deaconess Medical Center, Boston, MA 02215; ‡Gastrointestinal Unit (Medical Ser- of activated T cells, perhaps through recognition of CD1-associ- vices), Massachusetts General Hospital, Boston, MA 02116; and §Department of Mo- lecular Immunology, Graduate School of Medicine, Chiba University, Chuoku Chiba, ated ligands (for example, specific glycolipids) on their surface. Japan Significantly, both mouse and rat liver express CD1 (26, 27). The Received for publication March 24, 2000. Accepted for publication December present study was conducted to test the hypothesis that CD1 is 22, 2000. involved in T cell deletion, which we have done by inducing T cell The costs of publication of this article were defrayed in part by the payment of page activation and peripheral deletion in mice lacking CD1, and, there- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. fore, devoid of the CD1-reactive, largely TCR-invariant subset of NK T cells. The results show that peripheral T cell deletion was 1 This work was supported by National Institutes of Health Grants AI37554 (to I.N.C.) and AI42955 (to S.P.B.), and by an Howard Hughes Medical Institute Post- indeed impaired in CD1-deficient mice; however, this impairment doctoral Fellowship (to W.Z.M.). was not due to the lack of NK T cells. Furthermore, CD1 on the T 2 Address correspondence and reprint requests to Dr. I. Nicholas Crispe, The Center cells could not be acting as a target for a T cell deletion mecha- for Vaccine Biology and Immunology, The Aab Institute for Biomedical Research, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14620. E-mail ad- nism, because the requirement for CD1 expression was non-T cell dress: [email protected] autonomous. Therefore, we conclude that an interaction between Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 The Journal of Immunology 3091 the activated T cells and another cell expressing CD1 promotes the ␮g/ml DNase, and 5% FCS). After perfusion, the livers were homogenized deletion of activated peripheral T cells. by forcing through a metal strainer, and were then digested with 10 ml of digestion buffer at 37°C for 45 min. The hepatocytes were removed by centrifugation at 30 ϫ g for 3 min. The supernatant was centrifuged at Materials and Methods 650 ϫ g for 10 min to obtain a pellet of nonparenchymal cells. The pellet Mice from each liver was suspended with Bruff’s medium to a final volume of 1 ml, before mixing with 4 ml of 30% (w/v) metrizamide in PBS. The cell C57BL/6 (B6),3 (B6 ϫ 129)F or F , and ␤ -microglobulin-deficient mice 1 2 2 suspension in metrizamide was overlaid with serum-free Bruff’s medium, were purchased from The Jackson Laboratory (Bar Harbor, ME). CD1d- and centrifuged at 1500 ϫ g for 20 min. The cells at the interface were deficient mice (on the B6 ϫ 129 background) were created at Beth Israel collected, washed with PBS, and counted. Deaconess Hospital (Harvard University, Boston, MA). The J␣281-deficient mice were created at Chiba University (Chuoku Chiba, Japan). The mice were kept in the Immunobiology Mouse Unit at Yale Medical School Results (New Haven, CT), or at Beth Israel Deaconess Hospital. All mice were Defective peripheral T cell deletion used between 6–9 wk of age. The down-regulation of the TCR is a recognized feature of T cell Reagents activation leading to deletion, and has been previously reported in PE-coupled anti-NK1.1 Ab, PE-anti-mouse CD1 Ab, CyChrome-anti- peptide- and superantigen-induced peripheral T cell deletion (2, mouse TCR␣␤ Ab, biotinylated anti-hamster IgG, and strepavidin-PE were 10).

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