Harnessing the properties of dendritic cells in the pursuit of immunological tolerance

Abstract

The acquisition of self-perpetuating, immunological tolerance specific for graft alloantigens has long been described as the "holy grail" of clinical transplantation. By removing the need for life-long immunosuppression following engraftment, the adverse consequences of immunosuppressive regimens, including chronic infections and malignancy, may be avoided. Furthermore, autoimmune diseases and allergy are, by definition, driven by aberrant immunological responses to ordinarily innocuous antigens. The re-establishment of permanent tolerance towards instigating antigens may, therefore, provide a cure to these common diseases. Whilst various cell types exhibiting a tolerogenic phenotype have been proposed for such a task, tolerogenic dendritic cells (tol-DCs) are exquisitely adapted for antigen presentation and interact with many facets of the immune system: as such, they are attractive candidates for use in strategies for immune intervention. We review here our current understanding of tol-DC mediated induction and maintenance of immunological tolerance. Additionally, we discuss recent in vitro findings from animal models and clinical trials of tol-DC immunotherapy in the setting of transplantation, autoimmunity and allergy which highlight their promising therapeutic potential, and speculate how tol-DC therapy may be developed in the future.

Keywords: Allograft rejection; Autoimmunity; Dendritic cell; Immunotherapy; Regulatory T cell; Tolerance.

Fig. 1

Mechanisms of action of tol-DCs. The inhibition of T cell activation by tol-DCs has been attributed to various mechanisms that need not be mutually exclusive. These include Fas-FasL-mediated cell death of responding T cells, their functional paralysis through the induction of anergy or the polarisation of naïve T cells towards a regulatory phenotype through the secretion of anti-inflammatory cytokines such as IL-10 and TGF-β.

Fig. 2

The cycle of infections tolerance. Infectious tolerance, mediated through the activity of T_reg cells, is inherently self-sustaining: presentation of antigen by DCs in a suboptimal manner promotes the polarisation of naïve T cells towards an iT_reg phenotype capable of reinforcing the tolerogenicity of the DCs through secretion of TGF-β and IL-10. These cytokines may also act directly on naïve T cells recognising antigen de novo, thereby recruiting them to the pool of iT_reg cells.

Fig. 3

The role of DCs in the initiation of allograft rejection. Alloantigens expressed by the graft may be presented whole to the recipient T cell repertoire by DCs carried over in the graft as ‘passenger leukocytes’, a process known as the direct pathway. The recipient's own DCs may passively acquire foreign MHC molecules on their surface while patrolling the graft through the process of trogocytosis and induce allo-responses via the semi-direct pathway. In the indirect pathway, these same recipient DCs take up alloantigens shed by the graft and dying cells of donor origin and present them as processed peptides in a classical MHC-restricted manner.