title: Anti-coreceptor therapy drives selective T cell egress by suppressing inflammation-dependent chemotactic cues.
abstract: 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-γ 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.
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.|Precision BioSciences, Durham, North Carolina, USA.
authors: Aaron J
authors: AJ
authors: Martin
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
authors: Matthew
authors: M
authors: Clark
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
authors: Gregory
authors: G
authors: Gojanovich
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
authors: Fatima
authors: F
authors: Manzoor
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.|Department of Chemistry and Biochemistry, University of Mount Union, Alliance, Ohio, USA.
authors: Keith
authors: K
authors: Miller
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.|Committee on Immunology and Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, USA.
authors: Douglas E
authors: DE
authors: Kline
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.|Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland, USA.
authors: Y Maurice
authors: YM
authors: Morillon
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
authors: Bo
authors: B
authors: Wang
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
authors: Roland
authors: R
authors: Tisch
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D002633:Chemotaxis; D006801:Humans; D007249:Inflammation; D007515:Islets of Langerhans / Q000166:cytology; D051379:Mice; D016688:Mice, Inbred NOD; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors*
chemical_list: D000906:Antibodies; D011948:Receptors, Antigen, T-Cell