Reverse signaling using an inducible costimulator to enhance immunogenic function of dendritic cells

B7h, expressed by several cell types, binds ICOS expressed by activated T cells. We have previously shown that B7h triggering by ICOS-Fc inhibits human endothelial cell adhesiveness. This work investigated the effect of ICOS-Fc on human monocyte-derived dendritic cells (DCs). We found that DCs matured with LPS in the presence of ICOS-Fc (mDCsICOS) produced greater amounts of IL-23 and IL-10, and promoted a higher secretion of IL-17A and IL-17F in MLCs than did those DCs matured with LPS alone (mDCs). Moreover, mDCsICOS pulsed with the keyhole limpet hemocyanin Ag during the maturation phase were better stimulators of Ag-specific MHC class I–, but not class II–restricted T cells than mDCs. This was probably due to promotion of cross-presentation because it was not detected when the Flu-MA58–66 Ag was directly loaded on already matured DCs and mDCsICOS. Finally, ICOS-Fc inhibited the adhesion of both immature DCs and mDCs to vascular and lymphoid endothelial cells, their migratory activity, and the expression of the Rac-1 activator β-Pix involved in cell motility. These data suggest that B7h stimulation modulates DC function with effects on their maturation and recruitment into tissues. This opens a novel view on the use of interactors of the ICOS:B7h system as immunomodulatory drugs.

Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 59%

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Triggering of B7h by the ICOS Modulates Maturation and Migration of Monocyte-Derived Dendritic Cells

Occhipinti

Dianzani

Chiocchetti

et al. 2013

“…Moreover, we found that B7h triggering in human DCs increases the secretion of IL-23 (which is involved in Th17 expansion and survival) and supports Th17 cell activity (18). Finally, ICOS triggering in T cells (which is blocked by ICOS-Fc) is involved in the differentiation of both Tregs and Th17 cells (17,(31)(32)(33); however, its support of Treg differentiation prevails in the tumor environment (34,35).…”

Section: Discussionmentioning

confidence: 80%

B7h Triggering Inhibits the Migration of Tumor Cell Lines

Dianzani

Minelli

Gigliotti

et al. 2014

Vascular endothelial cells (ECs) and several cancer cells express B7h, which is the ligand of the ICOS T cell costimulatory molecule. We have previously shown that B7h triggering via a soluble form of ICOS (ICOS-Fc) inhibits the adhesion of polymorphonuclear and tumor cell lines to HUVECs; thus, we suggested that ICOS-Fc may act as an anti-inflammatory and antitumor agent. Because cancer cell migration and angiogenesis are crucial for metastasis dissemination, the aim of this work was to evaluate the effect of ICOS-Fc on the migration of cancer cells and ECs. ICOS-Fc specifically inhibited the migration of HUVECs, human dermal lymphatic ECs, and the HT29, HCT116, PC-3, HepG2, JR8, and M14 tumor cell lines expressing high levels of B7h, whereas it was ineffective in the RPMI7932, PCF-2, LM, and BHT-101 cell lines expressing low levels of B7h. Furthermore, ICOS-Fc downmodulated hepatocyte growth factor facilitated the epithelial-to-mesenchymal transition in HepG2 cells. Moreover, ICOS-Fc downmodulated the phosphorylation of focal adhesion kinase and the expression of β-Pix in both HUVECs and tumor cell lines. Finally, treatment with ICOS-Fc inhibited the development of lung metastases upon injection of NOD-SCID-IL2Rγnull mice with CF-PAC1 cells, as well as C57BL/6 mice with B16-F10 cells. Therefore, the B7h−ICOS interaction may modulate the spread of cancer metastases, which suggests the novel use of ICOS-Fc as an immunomodulatory drug. However, in the B16-F10–metastasized lungs, ICOS-Fc also increased IL-17A/RORc and decreased IL-10/Foxp3 expression, which indicates that it also exerts positive effects on the antitumor immune response.

“…Additionally, a CD4 + b 2 -microglobulin-dependent NOD T cell subset has been suggested to play a role in regulation diabetogenic BDC2.5 NOD CD4 + T cells (transferred to NOD.scid) via IFN-g-dependent modulation of host APCs (45 (34). It also remains a possibility that ICOS on CD4 + 24ab type II NKT cells could modulate DCs by binding ICOS-L on these cells, as it was reported that ligation of ICOS-L influenced the function of bone marrow-derived DCs (46). PD-1 and its ligands PD-L1 and PD-L2 play an important role in the control of T cell activation and peripheral tolerance (47).…”

Section: Discussionmentioning

confidence: 99%

CD4+ Type II NKT Cells Mediate ICOS and Programmed Death-1–Dependent Regulation of Type 1 Diabetes

Kadri

Korpos

Gupta

et al. 2012

Type 1 diabetes (T1D) is a chronic autoimmune disease that results from T cell-mediated destruction of pancreatic β cells. CD1d-restricted NKT lymphocytes have the ability to regulate immunity, including autoimmunity. We previously demonstrated that CD1d-restricted type II NKT cells, which carry diverse TCRs, prevented T1D in the NOD mouse model for the human disease. In this study, we show that CD4+ 24αβ type II NKT cells, but not CD4/CD8 double-negative NKT cells, were sufficient to downregulate diabetogenic CD4+ BDC2.5 NOD T cells in adoptive transfer experiments. CD4+ 24αβ NKT cells exhibited a memory phenotype including high ICOS expression, increased cytokine production, and limited display of NK cell markers, compared with double-negative 24αβ NKT cells. Blocking of ICOS or the programmed death-1/programmed death ligand 1 pathway was shown to abolish the regulation that occurred in the pancreas draining lymph nodes. To our knowledge, these results provide for the first time cellular and molecular information on how type II CD1d-restricted NKT cells regulate T1D.