B7x in the periphery abrogates pancreas-specific damage mediated by self-reactive CD8 T cells

Jun Sik Lee, Lisa Scandiuzzi, Anjana Ray, Joyce Wei, Kimberly A. Hofmeyer, Yael M. Abadi, P'ng Loke, Juan Lin, Jianda Yuan, David V. Serreze, James P. Allison, Xingxing Zang

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

B7x (B7-H4 or B7S1) is the seventh member of the B7 family, and its in vivo function remains largely unknown. Despite new genetic data linking the B7x gene with autoimmune diseases, how exactly it contributes to peripheral tolerance and autoimmunity is unclear. In this study, we showed that B7x protein was not detected on APCs or T cells in both human and mice, which is unique in the B7 family. Because B7x protein is expressed in some peripheral cells such as pancreatic β cells, we used a CD8 T cell-mediated diabetes model (AI4αb) in which CD8 T cells recognize an endogenous self-Ag, and found that mice lacking B7x developed more severe diabetes than control AI4αb mice. Conversely, mice overexpressing B7x in the b cells (Rip-B7xAI4αb) were diabetes free. Furthermore, adoptive transfer of effector AI4αb CD8 T cells induced diabetes in control mice, but not in Rip-B7xAI4αb mice. Mechanistic studies revealed that pathogenic effector CD8 T cells were capable of migrating to the pancreas but failed to robustly destroy tissue when encountering local B7x in Rip-B7xAI4αb mice. Although AI4αb CD8 T cells in Rip-B7xAI4αb and AI4αb mice showed similar cytotoxic function, cell death, and global gene expression profiles, these cells had greater proliferation in AI4αb mice than in RIP-B7xAI4αb mice. These results suggest that B7x in nonlymphoid organs prevents peripheral autoimmunity partially through inhibiting proliferation of tissue-specific CD8 T cells, and that local overexpression of B7x on pancreatic β cells is sufficient to abolish CD8 T cell-induced diabetes.

Original languageEnglish (US)
Pages (from-to)4165-4174
Number of pages10
JournalJournal of Immunology
Volume189
Issue number8
DOIs
Publication statusPublished - Oct 15 2012

    Fingerprint

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this