Consequences of direct and indirect activation of dendritic cells on antigen presentation: Functional implications and clinical considerations

Abstract

The antigen presentation properties of Dendritic cells (DC) are key factors in the initiation and modulation of immune responses. The mechanisms involved in the regulation of MHC II antigen presentation in DC have been thoroughly investigated. Here, we will summarize recent advances in the field, focusing on how DC regulate antigen presentation during and after maturation, and its functional implications. We will also discuss future perspectives and clinical considerations.

Introduction

Dendritic cells (DC) are distributed in peripheral tissues and lymphoid organs, where they are found in an immature state dedicated to sample their environment by a variety of endocytic mechanisms. They also express a wide range of receptors for pathogen products (e.g. Toll-Like Receptors (TLR)). Upon binding their ligands, these receptors activate the DC, triggering a differentiation program that culminates in the acquisition of a mature phenotype characterized by high surface expression of MHC class II (MHC II) and T cell co-stimulatory molecules (e.g. CD80, CD86 and CD40). A defining property of mature DC is that they can present with high efficiency and for prolonged periods antigens captured at the time of pathogen encounter, but they lose the capacity to present subsequently encountered antigens (Villadangos et al., 2005). This general model has been challenged in recent years by studies that show that DC that mature in response to pathogen products retain their capacity to present at least some form of antigen (Drutman and Trombetta, 2010, Platt et al., 2010). Furthermore, it is known that DC can also mature in response to inflammatory cytokines released during infections, and it seems that such DC retain their antigen presentation function largely intact (Simmons et al., 2012).

Characterization of the antigen presentation properties of mature DC is important for three reasons. Firstly, their function has traditionally been considered to induce immunity or tolerance toward antigens captured at the time and site of activation, but this notion may have to be revisited in light of the new advances. Secondly, the timing of DC activation after encounter with activating compounds (adjuvants) and antigen, and the subsequent changes induced by DC maturation, can dramatically affect the outcome of vaccination. Thirdly, certain pathologies such as sepsis, malaria infection, multiple trauma and severe burns induce systemic DC maturation and, as we have proposed, this may cause depletion of DC capable of presenting new antigens and contribute to the immunosuppression that accompanies these conditions (Njie et al., 2009, Villadangos et al., 2005, Young et al., 2007). Here we will summarize the current status of this area and possible future trends.