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Developmental Acquisition of the Lyn-CD22-SHP-1 Inhibitory Pathway Promotes B Cell Tolerance¹

Andrew J. Gross^*, Julia R. Lyandres, Anil K. Panigrahi, Eline T. Luning Prak and Anthony L. DeFranco^2,

^* Department of Medicine, Department of Surgery, and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104

To better understand whether autoimmunity in Lyn-deficient mice arises from compromised central or peripheral B cell tolerance, we examined BCR signaling properties of wild-type and Lyn-deficient B cells at different stages of development. Wild-type mature follicular B cells were less sensitive to BCR stimulation than were immature transitional stage 1 B cells with regard to BCR-induced calcium elevation and ERK MAPK activation. In the absence of Lyn, mature B cell signaling was greatly enhanced, whereas immature B cell signaling was minimally affected. Correspondingly, Lyn deficiency substantially enhanced the sensitivity of mature B cells to activation via the BCR, but minimally affected events associated with tolerance induction at the immature stage. The effects of CD22 deficiency on BCR signaling were very similar in B cells at different stages of maturation. These results indicate that the Lyn-CD22-Src homology region 2 domain-containing phosphatase-1 inhibitory pathway largely becomes operational as B cell mature, and sets a threshold for activation that appears to be critical for the maintenance of tolerance in the B cell compartment.

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 by National Institutes of Health Grant K08 AI52249 (to A.J.G.), by the Rosalind Russell Medical Research Center for Arthritis, and by National Institutes of Health Grant R01 AI20038 (to A.L.D.).

² Address correspondence and reprint requests to Dr. Anthony L. DeFranco, University of California, 400 Parnassus Avenue, Box 0414, San Francisco, CA 94143. E-mail address: anthony.defranco{at}ucsf.edu

³ Abbreviations used in this paper: SFK, Src family kinase; BM, bone marrow; [Ca²⁺]_i, intracellular Ca²⁺ concentration; HEL, hen egg lysozyme; mIg, membrane-bound Ig; NF, immature newly formed; SHP1, Src homology region 2 domain-containing phosphatase-1; T1, transitional stage 1; T2, transitional stage 2; T3, transitional stage 3; WT, wild type; RS, recombining sequence.

⁴ The online version of this article contains supplemental data.