title: Soluble OX40L and JAG1 Induce Selective Proliferation of Functional Regulatory T-Cells Independent of canonical TCR signaling.
abstract: Regulatory T-cells (Tregs) play a pivotal role in maintaining peripheral tolerance. Increasing Treg numbers/functions has been shown to ameliorate autoimmune diseases. However, common Treg expansion approaches use T-Cell Receptor (TCR)-mediated stimulation which also causes proliferation of effector T-cells (Teff). To overcome this limitation, purified patient-specific Tregs are expanded ex vivo and transfused. Although promising, this approach is not suitable for routine clinical use. Therefore, an alternative approach to selectively expand functional Tregs in vivo is highly desired. We report a novel TCR-independent strategy for the selective proliferation of Foxp3+Tregs (without Teff proliferation), by co-culturing CD4+ T-cells with OX40 L+Jagged(JAG)-1+ bone marrow-derived DCs differentiated with GM-CSF or treating them with soluble OX40 L and JAG1 in the presence of exogenous IL-2. Tregs expanded using soluble OX40 L and JAG1 were of suppressive phenotype and delayed the onset of diabetes in NOD mice. Ligation of OX40 L and JAG1 with their cognate-receptors OX40 and Notch3, preferentially expressed on Tregs but not on Teff cells, was required for selective Treg proliferation. Soluble OX40L-JAG1-induced NF-κB activation as well as IL-2-induced STAT5 activation were essential for the proliferation of Tregs with sustained Foxp3 expression. Altogether, these findings demonstrate the utility of soluble OX40 L and JAG1 to induce TCR-independent Treg proliferation.
authors.affiliation: Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA.
authors.forename: Prabhakaran
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA.
authors.forename: Khaled
authors.initials: K
authors.lastname: Alharshawi
authors.affiliation: Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA.
authors.forename: Palash
authors.initials: P
authors.lastname: Bhattacharya
authors.affiliation: Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Marinelarena
authors.affiliation: Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Haddad
authors.affiliation: Department of Immunology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
authors.forename: Zuoming
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chiba
authors.affiliation: Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Epstein
authors.affiliation: Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA.
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D000072100:Jagged-1 Protein / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053278:OX40 Ligand / Q000378:metabolism*; D000071656:Receptor, Notch3 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D053262:Receptors, OX40 / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D016328:NF-kappa B; C499374:NOTCH3 protein, human; D053278:OX40 Ligand; D000071656:Receptor, Notch3; D011948:Receptors, Antigen, T-Cell; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human