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Germ Line Deletion of the CD1 Locus Exacerbates Diabetes in the NOD Mouse

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Germ Line Deletion of the CD1 Locus Exacerbates Diabetes in the NOD Mouse Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse Fu-Dong Shi*, Malin Flodstro¨ m*, Balaji Balasa*†, Soon Ha Kim*, Kurt Van Gunst*, Jack L. Strominger‡, S. Brian Wilson§, and Nora Sarvetnick*¶ *Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; ‡Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138; and §Cancer Immunology and AIDS, Dana–Farber Cancer Institute, 44 Binney Street, Boston, MA 02115 Contributed by Jack L. Strominger, April 5, 2001 Quantitative and qualitative defects in CD1-restricted natural killer (11). To demonstrate the association of spontaneous autoim- T cells have been reported in several autoimmune-prone strains of munity in NOD mice with CD1d-restricted T cell depletion, we mice, including the nonobese diabetic (NOD) mouse. These defects have crossed CD1d-deficient mice to NOD and NOD͞BDC2.5 are believed to be associated with the emergence of spontaneous T cell receptor transgenic (tg) mice (12). The BDC2.5 T cell autoimmunity. Here we demonstrate that both CD1d-null NOD and antigen receptor (TCR) was cloned from an MHC class II- CD1d-null NOD͞BDC2.5 T cell receptor transgenic mice have an restricted T cell clone specific to an islet-derived antigen. Both accelerated onset and increased incidence of diabetes when com- CD1Ϫ/Ϫ NOD and CD1Ϫ/Ϫ NOD͞BDC2.5 mice have an accel- ؉ ؊ ؉ ؉ pared with CD1d / and CD1d / littermates. The acceleration of erated onset and increased incidence of diabetes when compared disease did not seem to result from changes in the T helper with their heterozygote and wild-type littermates. Therefore, (Th)1͞Th2 balance because lymphocytes purified from lymphoid CD1d-regulated events are critical to the maintenance of pe- organs and pancreatic islets of wild-type and CD1d-null mice ripheral tolerance in NOD mice. secreted equivalent amounts of IFN-␥ and IL-4 after stimulation. In contrast, the pancreata of CD1d-null mice harbored significantly Methods higher numbers of activated memory T cells expressing the Mice. Females from the NOD͞shi strain and NOD͞severe com- chemokine receptor CCR4. Notably, the presence of these T cells bined immunodeficient (SCID) mice were maintained at the was associated with immunohistochemical evidence of increased pathogen-free condition at The Scripps Research Institute (La destructive insulitis. Thus, CD1d-restricted T cells are critically Jolla, CA). CD1d-deficient mice (CD1Ϫ/Ϫ, with a disruption of important for regulation of the spontaneous disease process in both CD1.1 and CD1.2 genes; ref. 13) on a C57BL͞6 ϫ 129 sv NOD mice. background were crossed to NOD͞shi background, and off- spring from the 13th generation were intercrossed to obtain mice ype 1 diabetes mellitus (IDDM) is an autoimmune disorder homozygous for the CD1d-null mutation (NOD CD1Ϫ/Ϫ). Tcharacterized by lymphocyte-mediated destruction of insu- NOD͞BDC2.5 TCR mice (12) were backcrossed onto the NOD ␤ Ϫ Ϫ lin-producing cells in the pancreatic Islets of Langerhans (1, 2). background for 20 generations. The NOD CD1 / mice were At present, the primary immune defects that initiate the auto- crossed to NOD͞BDC2.5 mice and intercrossed to generate immune destruction of islets and that lead to IDDM remain CD1Ϫ/Ϫ NOD͞BDC2.5 and CD1ϩ/ϩ NOD͞BDC2.5 mice. Mice elusive. Studies with the nonobese diabetic (NOD) mouse model were considered diabetic after two consecutive measurements of of IDDM have revealed that multiple factors, in particular the nonfasting blood glucose level over 300 mg͞dl. presence or absence of regulatory cells, can affect the initiation of disease (1, 2). In mice, rats, and humans, a specific population Cell Transfer. Ten-week-old donor splenocyte suspensions were of regulatory T cells, the natural killer T cell (NKT) subset, have prepared (7) at a concentration of 108 cells per milliliter in PBS been suggested recently to play an important role in the pro- and injected i.v. into the 8-week-old NOD͞SCID females in a gression of autoimmune diabetes (3, 4). The regulatory functions total volume of 200 ␮l. of this population of T cells have been associated primarily with the CD1d-restricted subset (1, 3–5). CD1d is a nonpolymorphic Antigen and Antibody. The islet autoantigen glutamic acid decar- class Ib protein expressed on the cell surface of antigen pre- boxylase (GAD) was purified as described (14). Con A was senting cells, whose function is to present lipid antigens in its purchased from Sigma. For flow-cytometry analysis, purified or antigen-binding groove to CD1d-restricted T cells (3, 4). A role conjugated antibodies to mouse CD1, CD4, CD8, TCR ␣␤,V␤4, for CD1d-restricted T cells in the progression to IDDM was DX5 (pan NK marker), CD25, CD44, CD62L, and chemokine suggested by the findings of quantitative and qualitative defects receptors (CCR) 3, 4, and 5 were purchased from PharMingen. in these cells in both humans with type 1 diabetes (5, 6) and rodent models of IDDM—the diabetes-prone NOD mice and Histology. Sections of pancreas were examined histologically and the BioBreeding (BB) rat (4, 7–9). Furthermore, diabetes in stained with mAb to CD4, CD8, V␤4, Mac-1, and CD25, NOD mice can be inhibited partially through passive transfer of respectively (15). NKT cells enriched for CD1d-restricted T cells (10) or through the introduction of the V␣14J␣281 transgene, which increased the number of invariant CD1d-restricted cells (11). Abbreviations: GAD, glutamic acid decarboxylase; IDDM, insulin-dependent diabetes mel- IMMUNOLOGY Neither the passive transfer of cells enriched for CD1d- litus; NOD, nonobese diabetic; NKT, natural killer T; tg, transgenic; TCR, T cell antigen restricted T cells nor the introduction of the V␣14J␣281 trans- receptor; SCID, severe combined immunodeficient; CCR, chemokine receptor; Th, T helper. gene were able to protect NOD mice fully from diabetes (10, 11). †Present address: Autoimmunity and Inflammation, Protein Design Labs, 34801 Campus In the passive-transfer models, the infusion of thymic ‘‘NKT’’ Drive, Fremont, CA 94555. cells was significantly more efficacious than those lines derived ¶To whom reprint requests should be addressed at: Department of Immunology, IMM-23, The Scripps Research Institute, 10555 North Torrey Pines Road, La Jolla, CA 92037. E-mail: from the spleen, which conferred little or no protection on ␣ ␣ [email protected]. transfer (7). Moreover, in the V 14J 281 transgene model, only The publication costs of this article were defrayed in part by page charge payment. This 3 of 6 founder lines (those with the most robust and largest article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. numbers of NKT cells) were protected partially from diabetes §1734 solely to indicate this fact. www.pnas.org͞cgi͞doi͞10.1073͞pnas.121169698 PNAS ͉ June 5, 2001 ͉ vol. 98 ͉ no. 12 ͉ 6777–6782 Downloaded by guest on October 6, 2021 Table 1. Flow cytometric analysis of lymphocyte infiltration and cell activation status in control and CD1d-deficient NOD mice CD4ϩ CD8ϩ TCR␣␤ ϩ DX5, Mice n % CD25, % CD44, % CD62L, % CCR4, % CD25, % CD44, % CD62L, % CCR4, % Spleens CD1dϩ͞ϩ 5 4.1 Ϯ 0.2 7.3 Ϯ 1.5 20.2 Ϯ 4.9 66.3 Ϯ 4.5 38.2 Ϯ 6.6 5.2 Ϯ 1.5 17.5 Ϯ 2.5 68.7 Ϯ 2.5 13.7 Ϯ 3.4 CD1dϩ͞Ϫ 8 2.6 Ϯ 0.2 6.8 Ϯ 2.7 17.3 Ϯ 1.2 78.5 Ϯ 2.7 35.0 Ϯ 7.2 7.1 Ϯ 1.7 16.6 Ϯ 2.0 65.9 Ϯ 1.0 15.4 Ϯ 5.0 CD1dϪ͞Ϫ 8 0.1 Ϯ 0.0* 8.2 Ϯ 1.3 25.4 Ϯ 3.0 74.2 Ϯ 2.2 42.3 Ϯ 3.3 6.2 Ϯ 1.1 28.0 Ϯ 2.7 72.2 Ϯ 2.3 15.0 Ϯ 7.1 Pancreatic lymph nodes CD1dϩ͞ϩ 5 3.6 Ϯ 0.1 4.3 Ϯ 0.2 31.5 Ϯ 5.1 57.4 Ϯ 6.5 47.0 Ϯ 2.8 4.1 Ϯ 0.5 21.0 Ϯ 2.3 53.22 Ϯ 5.05 14.5 Ϯ 6.0 CD1dϩ͞Ϫ 8 2.0 Ϯ 0.1 4.2 Ϯ 0.4 27.3 Ϯ 3.8 66.5 Ϯ 8.7 51.3 Ϯ 8.0 6.3 Ϯ 1.0 26.6 Ϯ 1.8 60.00 Ϯ 6.31 18.3 Ϯ 6.1 CD1dϪ͞Ϫ 8 0.2 Ϯ 0.0* 5.2 Ϯ 0.3 30.2 Ϯ 2.9 68.2 Ϯ 3.4 58.2 Ϯ 4.2 7.2 Ϯ 0.2 32.5 Ϯ 4.7 77.05 Ϯ 5.60 20.2 Ϯ 4.4 Pancreata CD1dϩ͞ϩ 5 5.5 Ϯ 0.4 3.8 Ϯ 0.6 23.7 Ϯ 2.0 50.3 Ϯ 2.4 45.0 Ϯ 8.2 5.2 Ϯ 1.0 18.2 Ϯ 1.4 53.2 Ϯ 5.0 18.4 Ϯ 6.0 CD1dϩ͞Ϫ 8 2.2 Ϯ 0.2 4.1 Ϯ 0.4 29.6 Ϯ 2.8 62.2 Ϯ 2.1 52.5 Ϯ 6.3 7.0 Ϯ 3.2 29.3 Ϯ 2.8 40.0 Ϯ 3.1 25.2 Ϯ 4.5 CD1dϪ͞Ϫ 8 0.5 Ϯ 0.8* 8.7 Ϯ 0.6* 38.7 Ϯ 1.2* 55.5 Ϯ 6.1 77.2 Ϯ 4.4* 14.2 Ϯ 2* 32.5 Ϯ 5* 59.2 Ϯ 6.2 31.0 Ϯ 4* Mononuclear cells were isolated from spleens, pancreatic lymph nodes, and pancreata and labeled with mAbs as indicated. Data (mean Ϯ SD) shown in the table are derived from 8-week-old female mice.
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