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PTPN22 Deficiency Cooperates with the CD45 E613R Allele to Break Tolerance on a Non-Autoimmune Background¹

Julie Zikherman^*,,, Michelle Hermiston, David Steiner^||, Kiminori Hasegawa^#, Andrew Chan^# and Arthur Weiss^2,*,,,¶

^* Division of Rheumatology, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, Department of Pediatrics, ^¶ Howard Hughes Medical Institute, and ^|| Medical Scientist Training Program, University of California, San Francisco, CA 94143; and ^# Department of Immunology, Genentech, Inc., South San Francisco, CA 94080

Pep and CD45 are tyrosine phosphatases whose targets include the Src-family kinases, critical mediators of Ag receptor signaling. A polymorphism in PTPN22, the gene that encodes the human Pep orthologue Lyp, confers susceptibility to multiple human autoimmune diseases in the context of complex genetic backgrounds. However, the functional significance of the R620W risk allele is not clear. We report that misexpression of wild-type or R620W Pep/Lyp in Jurkat cells, in the context of its binding partner Csk, unmasks the risk allele as a hypomorph. It has been shown previously that although Pep-deficient mice on the B6 background have hyperresponsive memory T cells, autoimmunity does not develop. Mice containing a point mutation in the CD45 juxtamembrane wedge domain (E613R) develop a B cell-driven, lupus-like disease on the mixed 129/B6 background, but not on the B6 background. We studied the ability of Pep deficiency to act as a genetic modifier of the CD45 E613R mutation on the nonautoimmune B6 background to understand how complex susceptibility loci might interact in autoimmunity. In this study we report that double mutant mice develop a lupus-like disease as well as lymphadenopathy, polyclonal lymphocyte activation, and accelerated memory T cell formation. Following Ag receptor stimulation, peripheral B cells in the double mutant mice phenocopy hyperresponsive CD45 E613R B cells, whereas peripheral T cells respond like Pep^–/– T cells. These studies suggest that Pep^–/– T cells in the context of a susceptible microenvironment can drive hyperresponsive CD45 E613R B cells to break tolerance.

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 This work was supported in part by National Institutes of Health Grant POI AI 035297 (to A.W. and M.H.) and by a grant from the Arthritis Foundation (to J.Z.).

² Address correspondence and reprint requests to Dr. Arthur Weiss, Department of Medicine, Division of Rheumatology, Department of Microbiology and Immunology, 513 Parnassus Avenue, Room S-1032C, Box 0795, San Francisco, CA 94143-0795. E-mail address: aweiss{at}medicine.ucsf.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; DP, double positive; FO, follicular; LN, lymph node; PRS, proline-rich sequence; SFK, Src family kinase; SLE, systemic lupus erythematosus; WT, wild type.