Despite their enhanced presentation of pathogen-derived antigens, activated dendritic cells also present some self peptides, which could present a problem for the maintenance of self-tolerance. The T-cell receptor repertoire has, however, been purged of receptors that recognize self peptides presented in the thymus (see Chapter 8), so that T-cell responses against most ubiquitous self antigens are avoided. In addition, dendritic cells in the lymphoid tissues that have not been activated by infection will bear self-peptide:MHC complexes on their surface, derived from the breakdown of their own proteins and tissue proteins present in the extracellular fluid. Because these cells do not express the appropriate co-stimulatory molecules, however, they do not have the same capacity to activate naive T cells as do activated dendritic cells. Although the details are still unclear, the presentation of self peptides by lymph node-resident, or ‘unlicensed,’ dendritic cells may induce an alternative program of activation in naive T cells that favors immune regulation rather than immune activation.
Intracellular degradation of pathogens reveals pathogen components other than peptides that trigger dendritic cell activation. For example, bacterial or viral DNA containing unmethylated CpG dinucleotide motifs induces the rapid activation of plasmacytoid dendritic cells as a consequence of recognition of the DNA by TLR-9, which is present in intracellular vesicles (see Fig. 3.10). Exposure to unmethylated DNA activates NFκB and mitogen-activated protein kinase (MAPK) signaling pathways (see Figs. 7.19–7.21), leading to the production of pro-inflammatory cytokines such as IL-6, IL-12, IL-18, and interferon (IFN)-α and IFN-β by dendritic cells. In turn, these cytokines act on the dendritic cells themselves to augment the expression of co-stimulatory molecules. Heat-shock proteins are another internal bacterial constituent that can activate the antigen-presenting function of dendritic cells. Similarly, some viruses are recognized by TLRs inside the dendritic cell via double-stranded RNA produced during viral replication.
The induction of co-stimulatory activity in antigen-presenting cells by common microbial constituents is believed to allow the immune system to distinguish antigens borne by infectious agents from antigens associated with innocuous proteins, including self proteins. Indeed, many foreign proteins do not induce an immune response when injected on their own because they fail to induce co-stimulatory activity in antigen-presenting cells. When such protein antigens are mixed with bacteria, however, they become immunogenic, because the bacteria induce the essential co-stimulatory activity in cells that ingest the protein. Bacteria or bacterial components used in this way are known as adjuvants (see Appendix I, Section A-1). We will see in Chapter 15 how self proteins mixed with bacterial adjuvants can induce autoimmune disease, illustrating the crucial importance of the regulation of co-stimulatory activity in the discrimination of self from nonself.
interferons and may act as helper cells for antigen presentation by conventional dendritic cells.