Conference Scene: Antigen-Presenting Cells: Different Approaches to Immune Induction and Tolerance

Abstract

APCs are key players in the induction of T-cell responses. Accordingly, they have gained much attention as therapeutic targets for inflammatory diseases and cancer. Understanding their mode of action could serve in revealing novel approaches for the induction and blockade of T-cell immunity. This meeting has focused on recent advances in inducing the tolerogenic and immunostimulatory function of dendritic cells as well as current progress in the understanding of dendritic cell suppression through the CD4⁺ Treg cell function.

Sitting in the room named after the fathers of DNA structure, the mind travels back in time trying to grasp the huge impact from the discovery of Watson and Crick, which brought science into a new era. The unfolding of the DNA double helix secret was suddenly interrupted by the meeting chairs; Leonie Taams (King‘s College London, London, UK) and Catharien Hilkens (Newcastle University, Newcastle, UK) welcomed the delegates to the prestigious venue of the Royal College of Pathologists. To begin with, they highlighted the importance of APCs in T-cell-mediated immunity. Given that they orchestrate the promotion, differentiation and activation of T lymphoid cells, the elucidation of APC molecular mechanisms, in particular dendritic cells (DCs), will shed more light on novel ways for their induction and blockade. Many questions still exist concerning inflammatory diseases, like rheumatoid arthritis (RA), and cancer, where the control of immune responses still remains a challenge.

Tolerogenic & regulatory dendritic cells in RA

Catharien Hilkens advanced on the induction and administration of tolerogenic DCs (tolDCs) in RA. The answer is given by the interaction between DCs and T cells since improper signaling of either the MHC (signal 1), other co-stimulatory molecules (signal 2) or the cytokines (signal 3) results in the generation of Tregs and accordingly immune deprivation. Based on these observations, DCs constitute an elegant route for vaccine immunotherapy. A recently proposed protocol introduced by Hilkens generates tolDCs from CD14⁺ monocytes. Once incubated with IL4, GM-CSF and dexamethasone, CD14⁺ monocytes are converted into immature DCs on day 6 and transformed into tolDCs under the appropriate Toll-like receptor 4 ligand stimulation and vitamin D₃ on day 12 [1]. The Autologous Dendritic Cells in Rheumatoid Arthritis (AutoDECRA) Phase I study, using tolDCs generated from RA patients‘ CD14⁺ monocytes and administrated intra-articularly, will offer more precise conclusions [101].

Nevertheless, the central character of activated CD14⁺ monocytes in RA is highlighted by their interaction with both CD4⁺ T cells and Tregs at the inflamed joint. As Leonie Taams presented, Tregs modulate the apoptosis of activated CD14⁺ monocytes through the induction of Fas/CD95 expression. For that reason, monocyte interactions are critical for the pathogenesis of RA and their underlying pro- and anti-inflammatory mechanisms need to be expounded in detail. In this manner, the successful potency of treatment strategies will be increased. Continuing on DC treatment regimes for RA, David Escors (University College London, UK) introduced the selective activation of ERKs. The use of lentivectors to administer ERK activators promotes the suppression of CD8⁺ Tcell responses through the induction of regulatory DCs. Using an inflammatory arthritis model, Escors and his team have managed to generate human regulatory DCs using lentivectors which were sensitized with bovine serum albumin and complete Freund‘s adjuvant. Such intra-articular challenges lead to Treg expansion, control of inflammation and further protection from articular damage.

Tolerogenic dendritic cells & immune vaccines

Apart for inflammatory diseases, tolDCs appear to have promising applications in the immunosuppressive environment of tumors. The way that these responses may be boosted up, was discussed by Sandra Diebold (King‘s College London, UK), who proposed the use of viral pathogen-associated molecular patterns as adjuvants. In cancer, immature DCs are either partially activated or suppressed and, by mimicking the viral infection milieu, could stimulate the immune system to attack infected cells through strong cytotoxic responses. Furthermore, monocyte-derived DCs can be activated using Toll-like receptor agonists isolated from ascites fluid to enhance such responses. On a different perspective, boosting DC responses could be addressed indirectly via the limitation of Treg influence. Jagadeesh Bayry (Cordelier Research Center, Paris, France) introduced the use of vaccines to control the function and migration of Treg at the time of DC immunization. CCR4 appears as a conceivable target since it is expressed on Tregs but not naive T cells. CCR4 antagonists in combination with either Modified Vaccinia Ankara expressing Ag85A from Mycobacterium tuberculosis(MVA85A) or recombinant hepatitis B virus surface antigen (rHBsAg) vaccines are capable of blocking CCR4⁺ Treg migration and amplifying CD4⁺ T-cell proliferation in different experimental models [2].

Transplantation of insulin-producing β-cells of Langerhans islets is a new procedure that, for the moment, can be used for Type 1 diabetes treatment. Successful cell acceptance needs concomitant immunosuppression, which can be offered through TGF-β. As Maja Wallberg (Cambridge Institute for Medical Research, UK) suggested, a brief pulse of TGF-β expression can suppress DC activation and expression of CD80/CD86 co-stimulatory molecules in the graft while lowering the activation of both CD4⁺ and CD8⁺ T cells [3].

Instead of considering DC–Treg interactions as isolated events, it is worth viewing these cells as actors in the ‘tissue‘ scene. Blocking of Tcell function cannot solve the whole issue, thus induction and maintenance of a tolerogenic microenvironment is essential. Based on this concept, Steve Cobbold (University of Oxford, UK) intended a different approach in inducing tolerance in transplantation and autoimmunity models. Peripheral tolerance may be induced through the generation of antigen-specific Foxp3⁺ Tregs using a short treatment with monoclonal antibodies. Upon T-cell blockade, Tregs are able to maintain a tolerogenic microenvironment in the periphery through different mechanisms including cytokine release (e.g., TGF-β), amino acid catabolism (e.g., tryptophan) and adenosine generation [4].

Poster viewing

Recent progress in the field of APCs continued even during the recesses! While enjoying a coffee or a light lunch, attention was drawn to posters affixed around the room. Matthew Buck (University of Newcastle) presented his ongoing work regarding the ‘Isobaric Peptide Termini Labelling‘ strategy for quantitative proteomics of tolDCs. Different surface proteins on tolDC populations can be determined using growing media with heavy-isotoped amino acids labeled either on their N- or C-terminal. The use of adenosine receptors and the cAMP second messenger pathway to modulate human DCs was explained by Bruno Laguel (Cardiff University, Cardiff, UK). His team generated monocyte-derived DCs through stimulation of several immunomodulatory factors on their surface (e.g., CD25) using adenosine receptor agonists and cAMP-elevating agents. Consequently, DC differentiation was skewed towards a tolerogenic phenotype. A different group from Newcastle University, working on TNF receptors (TNFRs), discussed how TNFR1 and TNFR2 on the surface of DCs regulate their survival. Nicola Maney explained that stimulation of TNFR1, which is usually associated with proinflammatory signals, induces DC maturation and prevents apoptosis. On the other hand, TNFR2 does not enhance maturation signals. However, both receptors activate the classical (p65) and the alternative (p52) NFκB pathways even though TNFR1 appears to be more potent through p65 NFκB signaling. The central role of DCs in the initiation and progression of multiple sclerosis (MS) was the central theme of two posters. As Nathalie Cools (Antwerp University, Antwerp, Belgium) showed, there is emerging evidence that DCs, generated from MS patient monocytes, display an altered phenotype and function on T lymphocytes along with different migratory patterns. Such DCs express deviant migratory molecules, like CD62L, CCR5 and CCR7, whereas treatment with immunomodulatory cytokines (e.g., IL10) facilitates a tolerogenic phenotype. Apart from DC characterization, a different group studied the modulatory effects of vitamin D₃ on utilization of tolDCs to restore pathogenic responses in MS. “Monocyte-derived DCs treated with 1,25-dihydroxyvitamin D₃ not only differentiate into mature DCs but also display a maturation-resistant phenotype with impaired CD86, CD80, CD83 and HLA-DR upregulation,” said Wai-Ping Lee from Antwerp University. Accordingly, vitamin D₃ has put itself into the candidate group for MS treatment regimes. However, Yamini Bhusan Tripathi, from the Banaras Hindu University (Uttar Pradesh, India), drew most of the attention by introducing a different perspective of immunology according to the Ayurvedic system of Indian medicine. He postulated that immune responses depend on circadian rhythms and the three biological energies found throughout the body: “VATA – PITTA – KAPHA” (air – fire – water). Macrophages play an important role in these processes and several plant extracts, like Pueraria tuberosa DC, have been shown to influence their functions [5].

Conclusion

The central role of APCs in immune tolerance is well recognized and many studies are concentrated on new therapeutic strategies for inflammatory and tumor diseases. The direct approach concentrates on generating either tolDCs using monocytes with appropriate Toll-like receptor ligands or inducing regulatory DCs through ERK activators on lentivectors. In addition, DC function can be skewed indirectly using either vaccines or TGF-β, which limit the function and migration patterns of Tregs. Even though these approaches have yielded very promising results, important aspects are still concealed. The lack of biomarkers in defining tolerance and the controversy on how important antigen specificity is are emerging topics which have to be elucidated. As long as straight lines are drawn between tolerance induction and immune suppression, the future will shine more promising than ever before.

Information resources

This meeting was organized by EuroSciCon [102].

Financial & competing interests disclosure

N Nicolaou would like to acknowledge financial support for attendance at this meeting from EuroSciCon. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.