Bridging the Gap Between Tolerogenic Dendritic Cells In Vitro and In Vivo: Analysis of Siglec Genes and Pathways Associated with Immune Modulation and Evasion.

Abstract

Background/objectives: Dendritic cells (DCs) are master regulators of the adaptive immune response. Inflammatory DCs (inflamDCs) can prime inflammatory T cells in, for instance, cancer and infection. In contrast, tolerogenic DCs (tolDCs) can suppress the immune system through a plethora of regulatory mechanisms in the context of autoimmunity. We successfully generated tolDCs in vitro to durably restore immune tolerance to an islet autoantigen in type 1 diabetes patients in a clinical trial. However, cancers can induce inhibitory DCs in vivo that impair anti-tumor immunity through Siglec signaling.

Methods: To connect in vivo and in vitro tolDC properties, we tested whether tolDCs generated in vitro may also employ the Siglec pathway to regulate autoimmunity by comparing the transcriptomes and protein expression of immature and mature inflamDCs and tolDCs, generated from monocytes.

Results: Both immature DC types expressed most Siglec genes. The expression of these genes declined significantly in mature inflamDCs compared to mature tolDCs. Surface expression of Siglec proteins by DCs followed the same pattern. The majority of genes involved in the different Siglec pathways were differentially expressed by mature tolDCs, as opposed to inflamDCs, and in inhibitory pathways in particular.

Conclusions: Our results show that tolDCs generated in vitro mimic tumor-resident inhibitory DCs in vivo regarding Siglec expression.