Adenovirus-Mediated CCR7 and BTLA Overexpression Enhances Immune Tolerance and Migration in Immature Dendritic Cells

Abstract

Our previous report revealed that immature dendritic cells (imDCs) with adenovirus-mediated CCR7 overexpression acquired an enhanced migratory ability but also exhibited the lower immune tolerance observed in more mature cells. In the present study, we aimed to investigate whether BTLA overexpression was sufficient to preserve immune tolerance in imDCs with exogenous CCR7 overexpression. Scanning electron microscopy and surface antigens analysis revealed that BTLA overexpression suppressed DC maturation, an effect further potentiated in CCR7 and BTLA cooverexpressing cells. Correspondingly, in vitro chemotaxis assays and mixed lymphocyte reactions demonstrated increased migratory potential and immune tolerance in CCR7 and BTLA coexpressing cells. Furthermore, CCR7 and BTLA cooverexpressed imDCs suppressed IFN-γ and IL-17 expression and promoted IL-4 and TGF-beta expression of lymphocyte, indicating an increase of T helper 2 (Th2) regulatory T cell (Treg). Thus, these data indicate that CCR7 and BTLA cooverexpression imparts an intermediate immune phenotype in imDCs when compared to that in CCR7- or BTLA-expressing counterparts that show a more immunocompetent or immunotolerant phenotype, respectively. All these results indicated that adenovirus-mediated CCR7 and BTLA overexpression could enhance immune tolerance and migration of imDCs. Our study provides a basis for further studies on imDCs in immune tolerance, with the goal of developing effective cellular immunotherapies for transplant recipients.

Roles of BTLA in Immunity and Immune Disorders

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BTLA/HVEM Signaling: Milestones in Research and Role in Chronic Hepatitis B Virus Infection

“…Interestingly, an adenoviral infection can cause immature DCs to express high levels of CCR7 and exhibit relatively strong migration ability. However, their immune tolerance is relatively poor, and the overexpression of BTLA promotes the maintenance of immune tolerance in these DCs (57). Additionally, BTLA + DCs in the thymus increase the expression of CD5 in peripheral T-cells through the BTLA-HVEM signaling pathway and promote the differentiation of these CD5 + T-cells into Treg cells; thus, producing extrathymic T-cell tolerance (28).…”

Modulation of antigen presenting cell functions during chronic HPV infection

“…The chemokine receptor CCR7 is expressed by mature DCs and plays a role in mediating DC trafficking in response to LN homing CCL19 and CCL21 chemokines [103] . Upregulated expression of CCR7 on DCs within HPV-infected squamous epithelium and with a low level of co-stimulatory markers may induce migration of immunologically inactive DCs to draining LNs [104] . In addition, HR-HPV-positive cervical cancer cell lines induced monocyte recruitment and differentiation to immature DCs in vitro .…”