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T Cell Clonotype AI4 +CD8 the Induction of Diabetes by the Promiscuous Ford and H-2K B Requirement for Both H-2D

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T Cell Clonotype AI4 +CD8 the Induction of Diabetes by the Promiscuous Ford and H-2K B Requirement for Both H-2D Requirement for Both H-2Db and H-2Kd for the Induction of Diabetes by the Promiscuous CD8+ T Cell Clonotype AI4 This information is current as Toshiyuki Takaki, Scott M. Lieberman, Thomas M. Holl, of October 1, 2021. Bingye Han, Pere Santamaria, David V. Serreze and Teresa P. DiLorenzo J Immunol 2004; 173:2530-2541; ; doi: 10.4049/jimmunol.173.4.2530 http://www.jimmunol.org/content/173/4/2530 Downloaded from References This article cites 56 articles, 32 of which you can access for free at: http://www.jimmunol.org/content/173/4/2530.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 October 1, 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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Requirement for Both H-2Db and H-2Kd for the Induction of Diabetes by the Promiscuous CD8؉ T Cell Clonotype AI41 Toshiyuki Takaki,2* Scott M. Lieberman,2* Thomas M. Holl,‡ Bingye Han,§ Pere Santamaria,§ David V. Serreze,3‡ and Teresa P. DiLorenzo3*† The NOD mouse is a model for autoimmune type 1 diabetes in humans. CD8؉ T cells are essential for the destruction of the insulin-producing pancreatic ␤ cells characterizing this disease. AI4 is a pathogenic CD8؉ T cell clone, isolated from the islets of a 5-wk-old female NOD mouse, which is capable of mediating overt diabetes in the absence of CD4؉ T cell help. Recent studies using MHC-congenic NOD mice revealed marked promiscuity of the AI4 TCR, as the selection of this clonotype can be influenced by multiple MHC molecules, including some class II variants. The present work was designed, in part, to determine whether similar promiscuity also characterizes the effector function of mature AI4 CTL. Using splenocyte and bone marrow disease transfer models and in vitro islet-killing assays, we report that efficient recognition and destruction of ␤ cells by AI4 requires the Downloaded from ␤ cells to simultaneously express both H-2Db and H-2Kd class I MHC molecules. The ability of the AI4 TCR to interact with both H-2Db and H-2Kd was confirmed using recombinant peptide libraries. This approach also allowed us to define a mimotope peptide recognized by AI4 in an H-2Db-restricted manner. Using ELISPOT and mimotope/H-2Db tetramer analyses, we demonstrate for the first time that AI4 represents a readily detectable T cell population in the islet infiltrates of prediabetic NOD mice. Our identification of a ligand for AI4-like T cells will facilitate further characterization and manipulation of this pathogenic and promiscuous T cell population. The Journal of Immunology, 2004, 173: 2530–2541. http://www.jimmunol.org/ n both humans and NOD mice, type 1 diabetes (T1D)4 is an The CD8ϩ T cells contributing to the earliest stages of islet autoimmune disease that results from T cell-mediated de- inflammation represent several distinct antigenic specificities (7). I struction of insulin (INS)-producing pancreatic ␤ cells, and The AI4 CD8ϩ T cell clone, originally isolated from the islets of involves complex interactions among developmental, genetic, and a 5-wk-old female NOD mouse (3), represents one of these ␤ environmental factors (1). Although there are multiple susceptibil- cell-autoreactive specificities. NOD mice transgenically express- ity loci, the strong association of particular MHC class II mole- ing the AI4 TCR (designated NOD.AI4␣␤ transgenic (Tg)) ϩ cules with disease has led to extensive investigation of CD4 T progress to overt diabetes significantly earlier than nontransgenic cells in T1D (2). However, several studies in NOD mice have NOD mice (8). Strikingly, this accelerated diabetes development is by guest on October 1, 2021 ϩ documented the importance of pathogenic CD8 T cells in the also observed in NOD-scid.AI4␣␤ Tg, NOD.CD4null.AI4␣␤ Tg initial stages of ␤ cell destruction (3–6). (8), and NOD.Rag1null.AI4␣␤ Tg mice (7), all of which lack CD4ϩ T cells. Hence, naive AI4 T cells are able to develop, ma- ␤ Departments of *Microbiology and Immunology, and †Medicine (Division of Endo- ture, and mediate sufficient cell destruction to cause accelerated ϩ crinology), Albert Einstein College of Medicine, Bronx, NY 10461; ‡The Jackson disease in the complete absence of CD4 T cell help. AI4 repre- § Laboratory, Bar Harbor, ME 04609; and Department of Microbiology and Infectious sents the only diabetogenic CD8ϩ T cell clone known to be ca- Diseases, and Julia McFarlane Diabetes Research Centre, Faculty of Medicine, Health ϩ Sciences Centre, University of Calgary, Calgary, Alberta, Canada pable of doing so. In NOD mice, two other pathogenic CD8 T Received for publication April 27, 2004. Accepted for publication June 14, 2004. cell clones, 8.3 and G9C8, have been identified. NOD mice trans- The costs of publication of this article were defrayed in part by the payment of page genically expressing the diabetogenic 8.3 TCR (8.3-NOD) develop ϩ charges. This article must therefore be hereby marked advertisement in accordance accelerated diabetes that is enhanced by CD4 T cell help, as the with 18 U.S.C. Section 1734 solely to indicate this fact. frequency and rate of disease onset are greatly reduced in 8.3-NOD 1 This work was supported by National Institutes of Health Grants DK64315 (to mice lacking CD4ϩ T cells (9). The other known pathogenic T.P.D.), DK52956 (to T.P.D.), DK51090 (to D.V.S.), DK46266 (to D.V.S.), and ϩ DK20541 (Albert Einstein College of Medicine’s Diabetes Research and Training CD8 T cell clone, G9C8, has been shown to cause diabetes in the Center), and by grants from the Juvenile Diabetes Research Foundation (to T.P.D. and absence of CD4ϩ T cell help, but these experiments involved D.V.S.), the Alexandrine and Alexander Sinsheimer Foundation (to T.P.D.), the Ca- nadian Institutes of Health Research (to P.S.), and the Natural Sciences and Engi- transfer of previously activated G9C8 T cells into recipient mice; ϩ neering Research Council of Canada (to P.S.). S.M.L. is supported by National In- thus, their ability to develop and mature in the absence of CD4 T stitutes of Health Medical Scientist Training Grant GM07288. B.H. is supported by cell help is unknown (5). a postdoctoral fellowship from the Alberta Heritage Foundation for Medical Research (AHFMR). P.S. is a scientist of the AHFMR. The flow cytometry facility at Albert 8.3 recognizes an antigenic peptide derived from islet-specific Einstein College of Medicine is supported by National Institutes of Health Cancer glucose-6-phosphatase catalytic subunit-related protein Center Grant CA13330. (IGRP) , while G9C8 recognizes an INS B chain peptide 2 206–214 T.T. and S.M.L. contributed equally to this work. d (INS-B15–23), with both clones being H-2K -restricted (10, 11). 3 Address correspondence and reprint requests to Dr. Teresa P. DiLorenzo, Depart- We recently showed that AI4 recognizes a ␤ cell peptide (still ment of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail address: [email protected]; or unidentified) that is distinct from these two (7). Thus, AI4 repre- Dr. David V. Serreze, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME sents a third antigenic specificity contributing to early ␤ cell de- 04609. E-mail address: [email protected] struction in NOD mice. 4 Abbreviations used in this paper: T1D, type 1 diabetes; Tg, transgenic; IGRP, islet- ␣␤ specific glucose-6-phosphatase catalytic subunit-related protein; INS, insulin; GAD, Crosses between NOD.AI4 Tg mice and NOD stocks congenic glutamic acid decarboxylase; NRP, NOD-relevant peptide. for a variety of MHC haplotypes were recently used to determine Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 The Journal of Immunology 2531 whether the development of pathogenic CD8ϩ T cells could be af- Isolation of peptides from immunoaffinity-purified MHC class I fected by MHC variants within haplotypes known to dominantly in- H-2Kd and H-2Db molecules were immunoaffinity purified from 4 ϫ 109 hibit T1D (12). This work revealed that, when expressed on bone IFN-␥-treated NIT-1 pancreatic ␤ cells using the mAbs SF1-1.1 (anti-H- marrow-derived APC, MHC molecules within the H2nb1 and H2b 2Kd) and 28-14-8 (anti-H-2Db) (hybridomas from the American Type Cul- haplotypes, including one or both of the H2nb1-encoded class II mol- ture Collection) and their associated peptides extracted as previously de- ecules, could influence AI4 T cell selection through the induction of scribed (24). Peptide extracts were fractionated by reverse-phase HPLC as described (7). thymic deletion or anergy. Thus, the AI4 TCR is capable of tolero- genic interactions with a number of different MHC molecules during Peptide libraries and synthetic peptides T cell development. We now demonstrate that mature AI4 CTL also Positional scanning combinatorial peptide libraries (25), mimotope candi- exhibit promiscuous recognition of multiple peptide/MHC com- date peptides (including YFIENYLEL, designated Mim), and alanine-sub- plexes, and report the surprising finding that ␤ cell coexpression of stituted Mim peptides (including the F2A variant, designated MimA2) both H-2Db and H-2Kd is required for their efficient recognition and were purchased from Mimotopes (Clayton, Victoria, Australia).
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