NanoAPC deliver antigen, IL-2 and co-stimulatory molecules to antigen specific T cells and activate viral specific T cells in chronic infections

Abstract

The study of the immune system has provided insight in the mechanism of protection induced by vaccination; primarily that most clinically protective vaccines are potent in generating neutralizing antibody responses. However, vaccination fails to protect against a wide range of acquired chronic infections caused by viruses, such as HIV, HBV and HCV. One of the major reasons for weak responses to therapeutic vaccine is the impaired function of effector T cells resulting from viral persistence. Although IL-2 can potently increase effect function of viral specific T cells, systemic administration of IL-2 induces organ pathology and expansion of Treg cells. In this study, we have now developed a novel vaccine delivery system IL-2-nanoAPC delivering antigen-MHC complexes (pMHC), co-stimulatory molecules and IL-2 to antigen specific T cells. NanoAPC are derived from the endoplasmic reticulum (ER) membranes of human B cell line 721.221 engineered with selected HLA allele and IL-2 as the ER retention proteins. The IL-2-nanoAPC interacted with antigen specific T cells, induced immune synapses and expression of high affinity IL-2 receptor and enhanced effector function of antigen specific T cells, but did not affect bystander T cells and Foxp3+ Treg cells. Together with pMHC, co-stimulatory molecules, the selective delivery of IL-2 not only increased the CD4 and CD8 T cell responses to viral antigens but also enhanced TCR proximal signalling and suppressed expression of PD1 molecules on IFNγ producing effector CD8 T cells. We also found that the co-induction of T helper responses by IL-2-nanoAPC in a mixed culture could increase CD8 T cell responses to viral antigen. The IL-2-nanoAPC effectively induced responses of CD4 and CD8 T cells from chronic HBV patients. The results demonstrate that selective delivery of IL-2, together with pMHC and co-stimulatory molecules, by nanoAPC to antigen specific T cells has potential to recover anti-viral immune responses in chronic HBV patients.