B7x in the periphery abrogates pancreas-specific damage mediated by self-reactive CD8 T cells Journal Article
| Authors: | Lee, J. S.; Scandiuzzi, L.; Ray, A.; Wei, J.; Hofmeyer, K. A.; Abadi, Y. M.; Loke, P.; Lin, J.; Yuan, J.; Serreze, D. V.; Allison, J. P.; Zang, X. |
| Article Title: | B7x in the periphery abrogates pancreas-specific damage mediated by self-reactive CD8 T cells |
| 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. Copyright © 2012 by The American Association of Immunologists, Inc. |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; nonhuman; pancreas; cd8+ t lymphocyte; lymphocyte proliferation; cd8-positive t-lymphocytes; animal cell; mouse; animals; mice; mice, knockout; animal tissue; cell death; gene expression profiling; animal experiment; animal model; mice, inbred c57bl; mice, transgenic; disease severity; diabetes mellitus; antigen recognition; cytotoxic t lymphocyte; autoantigens; adoptive transfer; autoimmunity; lymphocytic infiltration; pancreas islet beta cell; antigen presenting cell; lymphocyte migration; lymphocyte antigen; diabetes mellitus, experimental; disease resistance; b7x protein; v-set domain-containing t-cell activation inhibitor 1 |
| Journal Title: | Journal of Immunology |
| Volume: | 189 |
| Issue: | 8 |
| ISSN: | 0022-1767 |
| Publisher: | The American Association of Immunologists, Inc |
| Date Published: | 2012-10-15 |
| Start Page: | 4165 |
| End Page: | 4174 |
| Language: | English |
| DOI: | 10.4049/jimmunol.1201241 |
| PUBMED: | 22972920 |
| PROVIDER: | scopus |
| PMCID: | PMC3466330 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 14 February 2013" - "CODEN: JOIMA" - "Source: Scopus" |
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