title: OX40L/Jagged1 cosignaling by GM-CSF-induced bone marrow-derived dendritic cells is required for the expansion of functional regulatory T cells.
abstract: Earlier, we had demonstrated that treatment with low dose of GM-CSF can prevent the development of experimental autoimmune thyroiditis (EAT), experimental autoimmune myasthenia gravis, and type 1 diabetes, and could also reverse ongoing EAT and experimental autoimmune myasthenia gravis. The protective effect was mediated through the induction of tolerogenic CD11C(+)CD8α(-) dendritic cells (DCs) and consequent expansion of Foxp3(+) regulatory T cells (Tregs). Subsequently, we showed that GM-CSF acted specifically on bone marrow precursors and facilitated their differentiation into tolerogenic dendritic cells (DCs; GM-CSF-induced bone marrow-derived DCs [GM-BMDCs]), which directed Treg expansion in a contact-dependent manner. This novel mechanism of Treg expansion was independent of TCR-mediated signaling but required exogenous IL-2 and cosignaling from DC-bound OX40L. In this study, we observed that OX40L-mediated signaling by GM-BMDCs, although necessary, was not sufficient for Treg expansion and required signaling by Jagged1. Concurrent signaling induced by OX40L and Jagged1 via OX40 and Notch3 receptors expressed on Tregs was essential for the Treg expansion with sustained FoxP3 expression. Adoptive transfer of only OX40L(+)Jagged1(+) BMDCs led to Treg expansion, increased production of IL-4 and IL-10, and suppression of EAT in the recipient mice. These results showed a critical role for OX40L- and Jagged1-induced cosignaling in GM-BMDC-induced Treg expansion.
authors: Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors: Anupama
authors: A
authors: Gopisetty
authors: Palash
authors: P
authors: Bhattacharya
authors: Christine
authors: C
authors: Haddad
authors: Joseph C
authors: JC
authors: Bruno
authors: Chenthamarakshan
authors: C
authors: Vasu
authors: Lucio
authors: L
authors: Miele
authors: Bellur S
authors: BS
authors: Prabhakar
mesh_terms: D000818:Animals; D060887:B7 Antigens / Q000276:immunology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008024:Ligands; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D053278:OX40 Ligand / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology*; D013967:Thyroiditis, Autoimmune / Q000276:immunology / Q000378:metabolism
chemical_list: D060887:B7 Antigens; D002135:Calcium-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D053278:OX40 Ligand; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
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