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), myasthenia gravis (EAMG) and type-1 diabetes; and could also reverse ongoing EAT and EAMG. The protective effect was mediated through the induction of tolerogenic CD11C+CD8α− DCs and consequent expansion of Foxp3+ T-regulatory cells (Tregs). Subsequently, we showed that GM-CSF acted specifically on bone marrow precursors and facilitated their differentiation into tolerogenic DCs (GM-BMDCs), which directed Treg expansion in a contact dependent manner. This novel mechanism of Treg expansion was independent of TCR mediated signalling but required exogenous IL-2 and co-signalling from DC bound OX40L. In the present study, we observed that OX40L mediated signalling by GM-BMDCs although necessary was not sufficient for Treg expansion and required signalling by Jagged1. Concurrent signalling 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 co-signalling in GM-BMDC-induced Treg expansion.

The role of T regulatory cells in immunopathogenesis of myasthenia gravis: implications for therapeutics

“…The ability of GM-CSF relating to maintain tolerogenic DCs, induction of FOXP3 + Tregs and suppress autoimmunity has been investigated by several studies [88][89][90]. GM-CSF is currently used in the treatment of neutropenia in cancer patients receiving chemotherapy [91].…”

Dendritic cells in autoimmune disorders and cancer of the thyroid

“…The DC -Tregs interaction was contact dependent and involved interaction of OX40L and Jagged1 molecules (expressed on DC surface) with their receptors on Tregs (OX40 and Notch3, respectively) [8,39]. Accordingly, only the OX40L + Jagged + DCs, upon adoptive transfer to EAT animals, were able to expand Tregs and suppress the clinical symptoms of the disease [8].…”

“…-DC population secreting high amounts of TGF-b and able to expand CD4 + CD25 + FoxP3 + Tregs in vitro [8,39]. The DC -Tregs interaction was contact dependent and involved interaction of OX40L and Jagged1 molecules (expressed on DC surface) with their receptors on Tregs (OX40 and Notch3, respectively) [8,39].…”

“…CD40, lymphotoxin-b receptor, OX40 ligand, 4-1BB ligand) [6]. However, multiple other DC costimulatory systems have been lately described including Serrate-like molecules (Jagged-1 and Jagged-2) which upon interaction with Notch receptor on T cells take part in regulatory T cell (Tregs) generation [7,8]. The DC maturation process encompasses also substantial changes in secretion profile of cytokines, chemokines and other humoral factors [2], as well as modification of activity of enzymes crucially involved in immune system function like indoleamine 2,3-dioxygenase (IDO) [9].…”

Basophil-associated OX40 Ligand Participates in the Initiation of Th2 Responses during Airway Inflammation

“…The antigen recognition by TCR, ligation of costimulatory molecules and corresponding cytokines such as IL-4 for Th2 cells are crucial for the induction of naïve T cells to effector Th2 cells. Recent studies suggest that OX40 (CD134)-OX40 ligand (OX40L, CD252) interaction contributes greatly to the differentiation of some Th subsets, such as Th9 cells, Th2 cells, and Tregs (13)(14)(15). OX40, a member of tumor necrosis factor receptor (TNFR) superfamily, is mainly expressed on activated T cells, including CD4…”