A specialist antigen storage compartment in dendritic cells to sustain cross-presentation.

Abstract

Dendritic cells (DCs) play a key role in inducing, shaping and maintaining adaptive immune responses. DCs act as professional antigen-presenting cells, uniquely able to prime the differentiation of naive T cells. DCs reside in all tissues of the body, collecting antigen for transport to the local draining lymph nodes and for presentation to a hugely diverse repertoire of T cells that recirculate between the blood and lymphoid organs. Crucially, DCs are capable of integrating signals from the tissue environment and instructing the development of appropriate T-cell responses. Thus, DCs represent a key link between the sensing of innate immune stimuli and the initiation of adaptive immune responses [1], as well as a means of transporting antigen from the periphery to inductive lymphoid compartments. Due to their central role in the regulation of immune responses, DCs represent a highly promising target for the development of immunological therapies. For example, in the fight against infectious disease, dendritic cell vaccination is capable of promoting increased immunogenicity of vaccines, especially in combination with other therapies [2]. Conversely, the functional plasticity of DCs also allows for the suppression of specific deleterious immune responses. Harnessing the tolerogenic potential of DCs can open up new therapeutic approaches for the treatment of inflammatory disorders, autoimmunity or allergy [3, 4]. Thus, efforts to study and understand DC biology remain at the forefront of medical, immunological and infectious disease research. A functional property of DCs that has generated particular interest for its therapeutic potential is their capacity for cross-presentation. Cross-presentation can be defined as the presentation of exogenous antigen on MHC class I to CD8+ T cells. This is a key step in the priming of effector CD8+ T cells, including cytotoxic T lymphocytes (CTLs), which are critical in the defence against intracellular pathogens, notably viruses, as well as in anti-tumour responses. In particular, a subset of DCs referred to as DC1 [5] have been shown to have a propensity for efficient cross-presentation, which appear to be evolutionarily conserved across multiple species [6]. Therefore, there is considerable interest in understanding how to target particular antigens for cross-presentation by DCs in order to generate antigen-specific antiviral and anti-tumour CTL responses. In this issue of Immunology, we present new research from Ho and colleagues [7], which characterizes the molecular and cellular mechanisms involved in antigen cross-presentation by DCs. Using fluorescent labelling and subcellular microscopy, the authors demonstrate antigen, in the form of immune complexes, can be detected in internal DC compartments after only 15 minutes of incubation. Highly efficient cross-presentation by DCs is then detected as early as 2h after antigen delivery. Crucially, the antigen is retained by DCs for at least 48h, allowing for continued cross-presentation to CD8+ T cells. Notably, the storage of antigen at early and late time-points appears to be handled by distinct subcellular compartments, which differ in terms of expression of several markers, as well as their distribution within the DC. The long-term storage compartments show expression of the lysosomal marker LAMP-1 and have a characteristic perinuclear localization. Furthermore, the authors demonstrate that targeting of antigen to a different initial uptake pathway (via C-type lectin) still results in the long-term storage of antigen in the same LAMP-1+ compartments. Interestingly, the authors detect no role for cathepsin S in the processing of internalized antigen for cross-presentation but suggest a hitherto uncharacterized role for cathepsin X in the process. Additionally, the authors find high expression of cathepsin X in the DC1 subset, further emphasizing its likely importance in cross-presentation. This new research may enable antigen to be targeted specifically to this LAMP-1+ compartment, and may therefore allow for long-term storage and extended cross-presentation of the antigen to CD8+ T cells. Combined with immunogenic stimuli, this could lead to a novel therapeutic approach to generating long-lasting and protective CTL responses against viral or tumour antigens.