Enhanced Dendritic Cell-Mediated Antigen-Specific CD4+ T Cell Responses: IFN-Gamma Aids TLR Stimulation.

Kuo-Ching Sheng,Mark D Wright,Stephanie Day,Vasso Apostolopoulos,Lily Stojanovska

doi:10.1155/2013/516749

Abstract

Phenotypic maturation and T cell stimulation are two functional attributes of DCs critical for immune induction. The combination of antigens, including those from cancer, with Toll-like receptor (TLR) ligands induces far superior cellular immune responses compared to antigen alone. In this study, IFN-gamma treatment of bone marrow-derived DC, followed by incubation with the TLR2, TLR4, or TLR9 agonists, enhanced DC activation compared to TLR ligation alone. Most notably, the upregulation of CD40 with LPS stimulation and CD86 with CpG stimulation was observed in in vitro cultures. Similarly, IFN-gamma coinjected with TLR ligands was able to promote DC activation in vivo, with DCs migrating from the site of immunization to the popliteal lymph nodes demonstrating increased expression of CD80 and CD86. The heightened DC activation translated to a drastic increase in T cell stimulatory capacity in both antigen independent and antigen dependent fashions. This is the first time that IFN-gamma has been shown to have a combined effect with TLR ligation to enhance DC activation and function. The results demonstrate the novel use of IFN-gamma together with TLR agonists to enhance antigen-specific T cell responses, for applications in the development of enhanced vaccines and drug targets against diseases including cancer.

Highlights

Vaccination requires highly purified proteins or synthetic peptides usually in combination with immune stimulating adjuvants or danger signals, to successfully prime T cells
Toll-like receptor (TLR) are essential receptors of the innate immune system which stimulate a vast array of inflammatory responses and eliminate invading pathogens
TLR7/8 agonists conjugated to HIV-1 Gag protein induce strong Th1/CD8+ T cell responses

Summary

Introduction

Vaccination requires highly purified proteins or synthetic peptides usually in combination with immune stimulating adjuvants or danger signals, to successfully prime T cells. DCs link the innate and adaptive immune responses by (i) binding a vast array of pathogens through their cell surface receptors, including C-type lectins, Toll-like receptors (TLRs), and scavenger receptors and inducing inflammatory responses for their elimination and (ii) are able to stimulate CD4+ T cell responses and cross present antigens for CD8+. Numerous strategies have been utilized to target antigens to DCs, following the abundance of information becoming available regarding cell surface expression of receptors and their role in stimulating immune responses [2]. The mannose receptor, DC-SIGN, scavenger receptor, DEC-205, and Toll-like receptors (TLRs) are amongst the most thoroughly studied DC receptors [2] Targeting of these receptors is becoming an effective strategy of delivering antigens in DC-based anticancer immunotherapy studies

Methods

Results

Conclusion