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Congenic Analysis of the NKT Cell Control Gene Nkt2 Implicates the Peroxisomal Protein Pxmp4¹

Julie M. Fletcher^2,*, Margaret A. Jordan^2,*, Sarah L. Snelgrove, Robyn M. Slattery, François D. Dufour^*, Konstantinos Kyparissoudis, Gurdyal S. Besra, Dale I. Godfrey and Alan G. Baxter^3,*

^* Comparative Genomics Centre, James Cook University, Townsville, Queensland, Australia; Monash University, Department of Immunology, Alfred Hospital Medical Research & Education Precinct, Melbourne, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia; and School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom

Type 1 NKT cells play a critical role in controlling the strength and character of adaptive and innate 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. Herein, we report the production and characterization of a NOD.Nkrp1^b.Nkt2b^b congenic mouse strain, which has increased thymic and peripheral NKT cells, a decreased incidence of type 1 diabetes, and enhanced cytokine responses in vivo and increased proliferative responses in vitro following challenge with -galactosylceramide. The 19 highly differentially expressed candidate genes within the congenic region identified by microarray expression analyses included Pxmp4. This gene encodes a peroxisome-associated integral membrane protein whose only known binding partner is Pex19, an intracellular chaperone and component of the peroxisomal membrane insertion machinery encoded by a candidate for the NKT cell control gene Nkt1. These findings raise the possibility that peroxisomes play a role in modulating glycolipid availability for CD1d presentation, thereby influencing NKT cell function.

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 with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A.G.B. and D.I.G. are supported by an Australian National Health and Medical Research Council (NHMRC) Research Fellowships, G.S.B. is the recipient of a Personal Research Chair from James Bardrick as a former Lister Institute-Jenner Research Fellow, J.M.F. is the recipient of an Australian Postgraduate Award, and M.A.J. and F.D.D. are recipients of James Cook University (JCU) intramural scholarships. This project was funded by the NHMRC, the Medical Genetics Research Advancement Program of JCU, the Medical Research Council (U.K.), The Wellcome Trust (U.K.), and Juvenile Diabetes Research Foundation Grant 1-2003-244.

² J.M.F. and M.A.J. contributed equally to this paper.

³ Address correspondence and reprint requests to Dr. Alan G. Baxter, Comparative Genomics Centre, James Cook University, Molecular Sciences Building 21, Townsville, Queensland 4811, Australia. E-mail address: Alan.Baxter{at}jcu.edu.au

⁴ Abbreviations used in this paper: -GalCer, -galactosylceramide; β₂m, β₂-microglobulin; NPC, Niemann-Pick type C disease; PPAR, peroxisome proliferator-activated receptor; SAP, SLAM-associated protein; SP, single positive.