B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance

Eric B. Wong, Chetna Soni, Alice Y. Chan, Phillip P. Domeier, Shwetank, Thomas Abraham, Nisha Limaye, Tahsin N. Khan, Melinda J. Elias, Sathi Babu Chodisetti, Edward K. Wakeland, Ziaur S.M. Rahman

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Signaling lymphocyte activation molecules (SLAMs) play an integral role in immune regulation. Polymorphisms in the SLAM family receptors are implicated in human and mouse model of lupus disease. The lupus-associated, somatically mutated, and class-switched pathogenic autoantibodies are generated in spontaneously developed germinal centers (GCs) in secondary lymphoid organs. The role and mechanism of B cell-intrinsic expression of polymorphic SLAM receptors that affect B cell tolerance at the GC checkpoint are not clear. In this study, we generated several bacterial artificial chromosome-transgenic mice that overexpress C57BL/6 (B6) alleles of different SLAM family genes on an autoimmune-prone B6.Sle1b background. B6.Sle1b mice overexpressing B6-derived Ly108 and CD84 exhibit a significant reduction in the spontaneously developed GC response and autoantibody production compared with B6.Sle1b mice. These data suggest a prominent role for Sle1b-derived Ly108 and CD84 in altering the GC checkpoint. We further confirm that expression of lupus-associated CD84 and Ly108 specifically on GC B cells in B6.Sle1b mice is sufficient to break B cell tolerance, leading to an increase in autoantibody production. In addition, we observe that B6.Sle1b B cells have reduced BCR signaling and a lower frequency of B cell-T cell conjugates; the reverse is seen in B6.Sle1b mice overexpressing B6 alleles of CD84 and Ly108. Finally, we find a significant decrease in apoptotic GC B cells in B6.Sle1b mice compared with B6 controls. Our study establishes a central role for GC B cell-specific CD84 and Ly108 expression in maintaining B cell tolerance in GCs and in preventing autoimmunity.

Original languageEnglish (US)
Pages (from-to)4130-4143
Number of pages14
JournalJournal of Immunology
Volume194
Issue number9
DOIs
StatePublished - May 1 2015

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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    Wong, E. B., Soni, C., Chan, A. Y., Domeier, P. P., Shwetank, Abraham, T., Limaye, N., Khan, T. N., Elias, M. J., Chodisetti, S. B., Wakeland, E. K., & Rahman, Z. S. M. (2015). B cell-intrinsic CD84 and Ly108 maintain germinal center B cell tolerance. Journal of Immunology, 194(9), 4130-4143. https://doi.org/10.4049/jimmunol.1403023