Journal
JCI INSIGHT
Volume 1, Issue 17, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.87636
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Funding
- NCI NIH HHS [P30 CA016086] Funding Source: Medline
- NIAID NIH HHS [R21 AI115752] Funding Source: Medline
- NIDDK NIH HHS [R01 DK100256] Funding Source: Medline
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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.
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