Codelivery of DNA Coding for the Soluble Form of CD86 Results in the Down-Regulation of the Immune Response to DNA Vaccines

The costimulatory pathway that includes CD80, CD86, CD28, and CTLA-4 plays a key role in regulating T cell activation and tolerance and is a promising therapeutic target. We have studied the possibility of down-regulating the immune response to DNA vaccine by codelivery of a plasmid coding for the extracellular domains of CD86 (pΔ86). We found that ΔCD86 was able to inhibit the engagement of FcCTLA-4 but not of FcCD28 to CD80 and CD86 expressed on COS cells. Coadministration of plasmid pΔ86 encoding for the extracellular domains of CD86 along with a plasmid encoding for the glycoprotein D (pgD) of herpes simplex virus-2 (a membrane-bound protein) by the im route in mice resulted in a strong inhibition of the cell-mediated immune response in the spleen and in draining lymph nodes. In addition, when pΔ86 was coadministered together with a plasmid encoding for the ovalbumin (pOVA) (a soluble protein), a strong inhibition of the cell-mediated immune response was observed in draining lymph nodes and only a partial inhibition was found in the spleen. Furthermore, only a partial down-regulation of the humoral immune response was observed. The mechanism involved could be a preferential engagement of ΔCD86 to CTLA-4 leading to the transmission of a negative signal to T lymphocytes.