Harnessing Human Cross-Presenting CLEC9A(+)XCR1(+) Dendritic Cells for Immunotherapy.

Kirsteen M Tullett,Mireille H Lahoud,Kristen J Radford

doi:10.3389/fimmu.2014.00239

Abstract

Dendritic cells (DC) are professional antigen presenting cells (APCs) that play a pivotal role in the induction and regulation of immune responses, including the induction of cytotoxic T lymphocyte (CTL) responses. They are an important focus for the development of vaccines against cancers and many pathogens, including HIV and malaria, where CTL responses are required for protection and disease eradication. DC loaded ex vivo with tumor antigen (Ag) have been administered as vaccines to cancer patients for over 15 years. They are well-tolerated and induce immune responses, including some clinical regressions, but there is clearly room for improvement (1). The DC network in both mice and humans is heterogeneous, with specialized DC subsets driving specific immune functions (2). New developments in our understanding of DC biology have identified a subset of DC characterized by the expression of novel markers CLEC9A (DNGR-1) (3, 4) and XCR1 (5, 6) as being important for the induction of CTL responses (7). Vaccine strategies that deliver Ag and activators directly to CLEC9A+XCR1+ DC in vivo promise to overcome many of the logistical issues associated with in vitro-derived vaccines, allowing precision and specificity of the desired immune response (8). Here, we discuss the biological properties of CLEC9A+XCR1+ DC that make them such attractive targets for CTL vaccines and new vaccine approaches to target them in vivo.

Highlights

Dendritic cells (DC) are professional antigen presenting cells (APCs) that play a pivotal role in the induction and regulation of immune responses, including the induction of cytotoxic T lymphocyte (CTL) responses
Increasing evidence points to a role for the mouse CD11b+ conventional DC (cDC) subset in the induction of CD4+ T cell responses a similar role for the equivalent human CD1c+ DC subset has not yet been established [2, 9]. It is the subset defined by expression of the C-type lectin-like receptor, CLEC9A, and the chemokine receptor, XCR1, that is crucial for the induction of CTL responses against cancers, viruses, and other pathogenic infections [2, 7]
CLEC9A+XCR1+ DC, CD1c+ DC, plasmacytoid DC (pDC), and MoDC have been shown to process and present Ag delivered by DEC-205 to CD4+ and CD8+ T cells in vitro [20, 31,32,33], limited direct comparisons suggest CLEC9A+ XCR1+ DC to be more effective at crosspresentation [20]

Summary

Introduction

Dendritic cells (DC) are professional antigen presenting cells (APCs) that play a pivotal role in the induction and regulation of immune responses, including the induction of cytotoxic T lymphocyte (CTL) responses. It is the subset defined by expression of the C-type lectin-like receptor, CLEC9A, and the chemokine receptor, XCR1, that is crucial for the induction of CTL responses against cancers, viruses, and other pathogenic infections [2, 7]. These features provide a strong rationale to develop technologies that deliver Ag to the cross-presentation pathway of CLEC9A+XCR1+DC in vivo.

Results

Conclusion