title: Ligation of cytotoxic T lymphocyte antigen-4 to T cell receptor inhibits T cell activation and directs differentiation into Foxp3+ regulatory T cells.
abstract: Cross-linking of ligand-engaged cytotoxic T lymphocyte antigen-4 (CTLA-4) to the T cell receptor (TCR) during the early phase of T cell activation attenuates TCR signaling, leading to T cell inhibition. To promote this event, a bispecific fusion protein comprising a mutant mouse CD80 (CD80w88a) and lymphocyte activation antigen-3 was engineered to concurrently engage CTLA-4 and cross-link it to the TCR. Cross-linking is expected to be attained via ligation of CTLA-4 first to MHCII and then indirectly to the TCR, generating a CTLA-4-MHCII-TCR trimolecular complex that forms between T cells and antigen-presenting cells during T cell activation. Treating T cells with this bispecific fusion protein inhibited T cell activation. In addition, it induced the production of IL-10 and TGF-β and attenuated AKT and mTOR signaling. Intriguingly, treatment with the bispecific fusion protein also directed early T cell differentiation into Foxp3-positive regulatory T cells (Tregs). This process was dependent on the endogenous production of TGF-β. Thus, bispecific fusion proteins that engage CTLA-4 and co-ligate it to the TCR during the early phase of T cell activation can negatively regulate the T cell response. Bispecific biologics with such dual functions may therefore represent a novel class of therapeutics for immune modulation. These findings presented here also reveal a potential new role for CTLA-4 in Treg differentiation.
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Karman
authors.forename: Ji-Lei
authors.initials: JL
authors.lastname: Jiang
authors.forename: Nathan
authors.initials: N
authors.lastname: Gumlaw
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhao
authors.forename: Juanita
authors.initials: J
authors.lastname: Campos-Rivera
authors.forename: Jose
authors.initials: J
authors.lastname: Sancho
authors.forename: Jinhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Canwen
authors.initials: C
authors.lastname: Jiang
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Yunxiang
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D060908:CTLA-4 Antigen / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006680:HLA Antigens / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006680:HLA Antigens; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases