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Published on: March 5, 2010
OX40 ligand regulates splenic CD8⁻ dendritic cell-induced Th2 responses in vivo
Fumitaka Kamachi1, Norihiro Harada2, Yoshihiko Usui3
1Department of Immunology, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Insights
OX40 ligand (OX40L) on CD8(-) dendritic cells is crucial for inducing T helper 2 (Th2) cell responses. This finding clarifies the mechanism behind Th2 cell differentiation mediated by antigen-pulsed CD8(-) dendritic cells in vivo.
Area of Science:
- Immunology
- Cell Biology
Background:
- Splenic conventional dendritic cells (cDCs) in mice are classified as CD8(-) and CD8(+) based on CD8α expression.
- Previous studies indicated that antigen-pulsed CD8(-) cDCs promote CD4 T cell differentiation into Th2 cells, but the underlying mechanism remains elusive.
Purpose of the Study:
- To investigate the role of OX40 ligand (OX40L) on CD8(-) cDCs in inducing Th2 responses.
- To elucidate the mechanism by which antigen-pulsed CD8(-) cDCs promote Th2 cell development in vivo.
Main Methods:
- Utilized OX40L-deficient cDCs and neutralizing anti-OX40L monoclonal antibody (mAb) in mouse models.
- Separated splenic cDCs into CD8(-) and CD8(+) populations.
- Stimulated cDCs with anti-CD40 mAb to induce OX40L expression.
Main Results:
- Injection of unseparated Ag-pulsed OX40L-deficient cDCs significantly reduced Th2 cytokine production (IL-4, IL-5, IL-10).
- OX40L expression on CD8(-) cDCs was inducible via anti-CD40 mAb stimulation.
- Administration of anti-OX40L mAb inhibited Th2 cytokine production induced by Ag-pulsed CD8(-) cDCs, including during secondary responses.
Conclusions:
- OX40L expressed on CD8(-) cDCs plays a physiological role in the development of Th2 cells.
- OX40L contributes to Th2 cell responses and secondary Th2 responses induced by Ag-pulsed CD8(-) cDCs in vivo.
Abstract:
In mice, splenic conventional dendritic cells (cDCs) can be separated, based on their expression of CD8α into CD8(-) and CD8(+) cDCs. Although previous experiments demonstrated that injection of antigen (Ag)-pulsed CD8(-) cDCs into mice induced CD4 T cell differentiation toward Th2 cells, the mechanism involved is unclear. In the current study, we investigated whether OX40 ligand (OX40L) on CD8(-) cDCs contributes to the induction of Th2 responses by Ag-pulsed CD8(-) cDCs in vivo, because OX40-OX40L interactions may play a preferential role in Th2 cell development. When unseparated Ag-pulsed OX40L-deficient cDCs were injected into syngeneic BALB/c mice, Th2 cytokine (IL-4, IL-5, and IL-10) production in lymph node cells was significantly reduced. Splenic cDCs were separated to CD8(-) and CD8(+) cDCs. OX40L expression was not observed on freshly isolated CD8(-) cDCs, but was induced by anti-CD40 mAb stimulation for 24 h. Administration of neutralizing anti-OX40L mAb significantly inhibited IL-4, IL-5, and IL-10 production induced by Ag-pulsed CD8(-) cDC injection. Moreover, administration of anti-OX40L mAb with Ag-pulsed CD8(-) cDCs during a secondary response also significantly inhibited Th2 cytokine production. Thus, OX40L on CD8(-) cDCs physiologically contributes to the development of Th2 cells and secondary Th2 responses induced by Ag-pulsed CD8(-) cDCs in vivo.
