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Nkt1 , the NKT Cell Control Gene Slamf1 Slamf1, the NKT Cell Control Gene Nkt1 Margaret A. Jordan, Julie M. Fletcher, Daniel Pellicci and Alan G. Baxter This information is current as J Immunol 2007; 178:1618-1627; ; of September 24, 2021. doi: 10.4049/jimmunol.178.3.1618 http://www.jimmunol.org/content/178/3/1618 Downloaded from References This article cites 43 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/178/3/1618.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 *average by guest on September 24, 2021 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 © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Slamf1, the NKT Cell Control Gene Nkt11 Margaret A. Jordan,2* Julie M. Fletcher,2* Daniel Pellicci,† and Alan G. Baxter3* Invariant NKT cells play a critical role in controlling the strength and character of adaptive immune responses. We have previously reported deficiencies in the numbers and function of NKT cells in the NOD mouse strain, which is a well-validated model of type 1 diabetes and systemic lupus erythematosus. Genetic control of thymic NKT cell numbers was mapped to two linkage regions: Nkt1 on distal chromosome 1 and Nkt2 on chromosome 2. In this study, we report the production and charac- terization of a NOD.Nkrp1b.Nkt1b congenic mouse strain, apply microarray expression analyses to limit candidate genes within the 95% confidence region, identify Slamf1 (encoding signaling lymphocyte activation molecule) and Slamf6 (encoding Ly108) as potential candidates, and demonstrate retarded signaling lymphocyte activation molecule expression during T cell development of NOD mice, resulting in reduced expression at the CD4؉CD8؉ stage, which is consistent with decreased NKT cell production and deranged tolerance induction in NOD mice. The Journal of Immunology, 2007, 178: 1618–1627. Downloaded from nvariant NKT (iNKT)4 cells are an immunoregulatory pop- mosome 1 that control NKT cell numbers, we produced and char- ulation of lymphocytes that plays a critical role in controlling acterized a NOD mouse line congenic for the C57BL/6 allele at the I the adaptive immune system and contributes to the regulation Nkt1 locus. of autoimmune responses (1–3). We have previously reported de- ficiencies in the numbers and function of NKT cells in the NOD Materials and Methods Mice mouse strain (4, 5), which is a well-validated model of type 1 http://www.jimmunol.org/ diabetes (6) and systemic lupus erythematosus (7, 8), and mapped NOD.Nkrp1b, C57BL/6J, and congenic mice were maintained at the Im- genetic control of thymic NKT cell numbers in a first backcross munogenetics Research Facility at the James Cook University in specific (BC1) from C57BL/6 to NOD.Nkrp1b mice (9). The numbers of pathogen-free conditions. The NOD.Nkrp1b strain carries B6-derived al- leles at the NK complex on chromosome 6 (from D6mit105 to D6mit135), thymic NKT cells of 320 BC1 mice were determined by fluores- b b ␣ permitting the use of the NK1.1 marker (13, 14). NOD.Nkrp1 .Nkt1 mice cence-activated cell analysis using CD1d/ -galactosylceramide were produced by intercrossing NOD.Nkrp1b and C57BL/6J mice and per- (CD1d/␣-GalCer) tetramer (10). Tail DNA of 138 female BC1 forming serial backcrosses to NOD.Nkrp1b to N10, before intercrossing mice was analyzed for PCR product length polymorphisms at 181 and selection of homozygous congenic founders. These studies have been simple sequence repeats, providing Ͼ90% coverage of the auto- reviewed and approved by the James Cook University Institutional Animal Care and Ethics Committee. somal genome with an average marker separation of 8 cM. Two by guest on September 24, 2021 loci exhibiting significant linkage to NKT cell numbers were iden- DNA preparation tified; the most significant (Nkt1; log-likelihood ratio 6.82) was Extraction of genomic DNA from NOD.Nkrp1b, NOD.Nkrp1b.Nkt1b, mapped near D1mit15 on distal chromosome 1 (9) in the same and C57BL/6 mouse strains was conducted using the CAS-1810 X- region as the NOD mouse lupus susceptibility gene Babs2/Bana3 TractorGene (Corbett Robotics) and the XTR2 X-tractor gene solid sample (11). The second locus (Nkt2; log-likelihood ratio 4.90) was reagent pack (Sigma-Aldrich), which is based on a method developed in mapped between D2mit490 and D2mit280 on chromosome 2 (9) in this laboratory. Briefly, DNA was extracted by digesting an 11-mm tailtip in 400 ␮l of digest buffer (100 mM Tris-HCl (pH 8), 10 mM EDTA, 100 the same region as Idd13, a NOD-derived diabetes susceptibility mM NaCl, 0.5%SDS, 50 mM DTT, and 100 mM proteinase K), O/N, 56°C, gene (12). In an attempt to identify the genetic sequences on chro- 40 rpm in a VORTEMP 56EVC (Labnet). Samples were lysed by addition of 700 ␮l of 5.25 M guanidine thiocyanate lysis buffer (5.25 M guanidine thiocyanate, 10 mM Tris-HCl (pH 6.5), 20 mM EDTA, 4% Triton X-100, *Comparative Genomics Center, James Cook University, Townsville, Queensland, and 64.8 mM DTT), loaded on a glass filter (GF/B) polypropylene micro- Australia; and †University of Melbourne, Department of Microbiology and Immu- plate (Whatman International), and washed twice in propanol wash buffer nology, Parkville, Victoria, Australia and once in 100% ethanol. Samples were eluted in 150 ␮l of elution buffer. Received for publication January 19, 2006. Accepted for publication November The DNA yield was quantified spectrophotometrically. 21, 2006. Genotyping 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 Identification of the congenic segment boundaries and the background with 18 U.S.C. Section 1734 solely to indicate this fact. screen were conducted by genotyping the extracted tail DNA using simple 1 A.G.B. is supported by an Australian National Health and Medical Research Coun- sequence repeats chosen from the Whitehead Institute simple sequence cil Senior Research Fellowship, J.M.F. is the recipient of an Australian Postgraduate length polymorphism library, as well as markers designed in-house on the Award, and M.A.J. is the recipient of a James Cook University intramural scholarship. basis of PCR product length polymorphisms between C57BL/6 and This project was funded by the Australian National Health and Medical Research NOD/Lt strains, as described previously (9). Council. RNA preparation and microarray expression analyses 2 M.A.J. and J.M.F. contributed equally to this manuscript. 3 Address correspondence and reprint requests to Dr. Alan G. Baxter, Comparative To minimize activation of the apoptosis cascade, thymi were removed from Genomics Center, Molecular Sciences Building 21, James Cook University, Towns- 4-wk-old female mice and placed in RNA-later (Qiagen) within 120 s of ville, Queensland 4811, Australia. E-mail address: [email protected] the mouse being placed in CO2 for asphyxiation. In our hands, this pro- 4 Abbreviations used in this paper: iNKT, invariant NKT; CD1d/␣-GalCer, CD1/␣- cedure substantially improved the signal to noise ratio of expression anal- galactosylceramide; DP, double positive; SAP, SLAM-associated protein; SH, Src ysis, greatly reducing the numbers of differentially expressed genes homology; SLAM, signaling lymphocyte activation molecule; SP, single positive. identified. The thymi were individually homogenized in the RLT buffer of an Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 RNeasy kit (Qiagen), with contamination minimized by extensive washing www.jimmunol.org The Journal of Immunology 1619 FIGURE 1. Characterization of the NOD.Nkrp1b.Nkt1b congenic mouse line. The boundaries of the Nkt1 congenic segment on distal chromosome 1 are indicated (A). Proportions (B) and absolute numbers (C) of thymic NKT cell numbers in 5-wk-old mice from the congenic line and the NOD.Nkrp1b parental line as determined by CD1d/␣-GalCer tetramer binding are shown. Values for NOD.Nkrp1b mice are indicated by Ⅺ whereas those for NOD.Nkrp1b.Nkt1b mice by ࡗ. Proportion means and SEM are shown, whereas for numbers, individual values and statistical analysis (Mann-Whitney U test) are given. with RNase-off and RNase-free-DNase-free-water between samples. Ho- 5Ј-ATTTTGCTCTTGTCTCTGC-3Ј, and R primer, 5Ј-GGAATCCCTCTT mogenates were passed through Qiashedder columns (Qiagen) and ex- TAGGTAGACTGC-3Ј; and Gapdh, F primer, 5Ј-ACCACAGTCCATGC tracted (RNeasy; Qiagen). The RNA yield was quantified spectrophoto- CATCACT-3Ј, and R primer, 5Ј-TCCACCACCCTGTTGCTGTA-3Ј. metrically and aliquots electrophoresed for determination of sample Titrated template standards were processed in parallel with unknown Downloaded from concentration and purity. controls. Expression microarray hybridizations were performed by the Australian Genome Research Facility using the one-cycle cDNA synthesis kit (Af- Primer design and sequencing fymetrix) and Affymetrix 430 2.0 mouse gene microarray, which contains Ͼ45,000 probe sets, representing Ͼ34,000 well-substantiated mouse Primers for sequencing were designed using BioTechnix 3d 1.1.0, based on genes. sequence obtained from UCSC Genome Bioinformatics (http://genome. The probed arrays were scanned using the GeneChip Scanner 3000, and ucsc.edu) such that overlapping sequences would be amplified across the the images (.dat files) were processed using GeneChip Operating System promoter, coding, and noncoding mRNA sequences.
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