Designing vaccines based on biology of human dendritic cell subsets

Abstract

The effective vaccines developed against a variety of infectious agents, including polio, measles, and hepatitis B, represent major achievements in medicine. These vaccines, usually composed of microbial antigens, are often associated with an adjuvant that activates dendritic cells (DCs). Many infectious diseases are still in need of an effective vaccine including HIV, malaria, hepatitis C, and tuberculosis. In some cases, the induction of cellular rather than humoral responses may be more important because the goal is to control and eliminate the existing infection rather than to prevent it. Our increased understanding of the mechanisms of antigen presentation, particularly with the description of DC subsets with distinct functions, as well as their plasticity in responding to extrinsic signals, represent opportunities to develop novel vaccines. In addition, we foresee that this increased knowledge will permit us to design vaccines that will reprogram the immune system to intervene therapeutically in cancer, allergy, and autoimmunity.

Figure 1. Dendritic cells

DCs reside in the tissue where they are poised to capture antigens, be it microbes or vaccines. DCs recognize microbes (vaccines), and secrete cytokines (e.g. IFN-α), directly through pattern recognition receptors, or indirectly through stromal cells that sense microbes (vaccines). Cytokines secreted by DCs in turn activate effector cells of innate immunity such as eosinophils, macrophages and NK cells. Activation triggers DCs migration towards secondary lymphoid organs and simultaneous activation (maturation). These migratory DCs display antigens in the context of classical MHC class I and class II or non-classical CD1 molecules, which allow selection of rare antigen-specific T lymphocytes. Activated T cells drive DCs towards their terminal maturation, which induces further expansion and differentiation of lymphocytes. Activated T lymphocytes traverse inflamed epithelia and reach the injured tissue, where they eliminate microbes and/or microbe-infected cells. B cells, activated by DCs and T cells, differentiate into plasma cells that produce antibodies against the initial pathogen. Antigen can also drain into lymph nodes without involvement of peripheral tissue DCs and be captured and presented by lymph node resident DCs. Antigen capture by interstitial DCs (intDCs; orange) will preferentially lead to generation of humoral immunity whereas antigen capture by Langerhans cells (LCs; green) will preferentially lead to generation of cellular immunity.

Figure 2. Distinct DC subsets generate distinct types of T cell immunity

DC system has two cardinal features: 1) subsets; and 2) plasticity. This yields distinct types of immunity thereby allowing DCs to cope with protection against a variety of microbes and maintenance of tolerance to self. Understanding these two features is fundamental to develop vaccines that elicit the desired type of immune responses.

Figure 3. Many roads lead to DC maturation

DCs exist in distinct functional states, resting and activated, or immature and mature. Depending on the signal DCs will undergo activation/maturation, the quality of which will determine the type of elicited adaptive immunity.

Figure 4. Understanding human myeloid dendritic cell subsets for the rational design of DC-targeting vaccines

Novel vaccines rely on rational immunological approaches and aim at activating both the cellular and the humoral arm. We envision that targeting antigens and activation of distinct mDC subsets, with different specializations, will result in the generation of a broad and long lived immune protection. Thus, the most efficient vaccines might be those that will target both LCs and dermal CD14⁺ DCs thereby allowing the maximal stimulation of cellular and humoral immune responses and the generation of long-term memory protection.

Figure 5. Approaches to DC-based therapeutic vaccination in cancer and chronic infections

1) Vaccines based on antigen with or without adjuvant that target DCs randomly. That might result in vaccine antigens being taken up by a “wrong” type of DCs in the periphery which might lead to “unwanted” type of immune response. Vaccine antigens could also flow to draining lymph nodes where they can be captured by resident DCs; 2) Vaccines based on ex-vivo generated antigen-loaded cytokine-driven DCs that are injected back into patients; and 3) specific in vivo DC targeting with anti-DC antibodies linked (by fusion or conjugation) fused antigens and with DC activators. 4) Next generation clinical trials will test optimized DC vaccines combined with patient-adjusted approaches to block Tregs and to breakdown the suppressive tumor environment. These therapies will be tested in pre-selected patients thereby leading to personalized therapy.