Dendritic cells and the control of immunity: enhancing the efficiency of antigen presentation

Relevant antigens often are known for diseases that involve the immune system. Yet purified antigens by themselves do not control immunity, especially T-cell immunity. For example, many antigens have been defined for HIV-1 and melanoma, but good HIV-1 vaccines and melanoma immune therapies are lacking. Dendritic cells (DCs) are important intermediaries between antigens and better control of the immune system.

Some properties that allow DCs to control immunity are reviewed, followed by new studies using DCs as adjuvants in humans. An emerging area is then detailed, the special mechanisms whereby DCs enhance the formation of ligands for T-cells, i.e., complexes of major histocompatibility complex (MHC) products and antigenic peptides.

Once criteria were developed to identify and isolate DCs, several functional properties became evident. DCs are unusually potent in initiating T-cell mediated immunity in culture. In vivo, DCs are positioned to capture antigens and migrate to T-cell areas of lymphoid organs. There, DCs are able to prime animals, controlling the MHC restriction of the primed T-cells and inducing resistance to pathogens. DCs pulsed ex vivo with antigens are now being used to induce and expand T-cell immunity in humans. To optimize their use, two areas of DC function need to be harnessed: their terminal differentiation or maturation, and antigen uptake. DCs capture most types of antigens at an immature stage of development, but the cells must receive additional stimuli prior to acquiring potent T-cell stimulatory activity. Stimuli from microbes, inflammation and trauma mature DCs. These change the DCs in several ways, even inducing the formation of MHC II-peptide complexes or T-cell receptor (TCR) ligands. The latter move to the surface in nonlysosomal vesicles that simultaneously carry CD86 costimulatory molecules for T-cell activation. Both MHC and CD86 remain co-clustered in patches at the DC surface. DCs also express a receptor, DEC-205, that enhances antigen uptake and presentation. DEC-205 recycles in an unusual manner through MHC class II-rich, late endosomes or lysosomes, dramatically increasing the presentation of bound ligands. Additionally and importantly, DCs can process dying cells and immune complexes onto MHC class I products, events that are termed the "exogenous pathway" or "cross presentation."

The control of the immune system by DCs reflects numerous specializations, not a single "magic bullet." These specializations include a number of mechanisms that increase the efficiency of antigen uptake and MHC-peptide complex formation. The harnessing of these and other features of DCs provides opportunities for improving immune-based therapies and vaccine design.