| First Author | Martin AJ | Year | 2016 |
| Journal | JCI Insight | Volume | 1 |
| Issue | 17 | Pages | e87636 |
| PubMed ID | 27777971 | Mgi Jnum | J:290721 |
| Mgi Id | MGI:6443376 | Doi | 10.1172/jci.insight.87636 |
| Citation | Martin AJ, et al. (2016) Anti-coreceptor therapy drives selective T cell egress by suppressing inflammation-dependent chemotactic cues. JCI Insight 1(17):e87636 |
| abstractText | There continues to be a need for immunotherapies to treat type 1 diabetes in the clinic. We previously reported that nondepleting anti-CD4 and -CD8 Ab treatment effectively reverses diabetes in new-onset NOD mice. A key feature of the induction of remission is the egress of the majority of islet-resident T cells. How this occurs is undefined. Herein, the effects of coreceptor therapy on islet T cell retention were investigated. Bivalent Ab binding to CD4 and CD8 blocked TCR signaling and T cell cytokine production, while indirectly downregulating islet chemokine expression. These processes were required for T cell retention, as ectopic IFN-gamma or CXCL10 inhibited Ab-mediated T cell purging. Importantly, treatment of humanized mice with nondepleting anti-human CD4 and CD8 Ab similarly reduced tissue-infiltrating human CD4(+) and CD8(+) T cells. These findings demonstrate that Ab binding of CD4 and CD8 interrupts a feed-forward circuit by suppressing T cell-produced cytokines needed for expression of chemotactic cues, leading to rapid T cell egress from the islets. Coreceptor therapy therefore offers a robust approach to suppress T cell-mediated pathology by purging T cells in an inflammation-dependent manner. |
