Dendritic-cell control of pathogen-driven T-cell polarization

Key Points Pathogens initiate adaptive immunity by activating immature dendritic cells (DCs) that mature into immuno-stimulatory effector cells and provide naive T cells with first, antigen that stimulates T cells with relevant T-cell receptors (TCRs); second, co-stimulation, which prevents the development of tolerance; and third, polarizing signals that determine the class of immune response. Pathogens express pathogen-associated molecular patterns (PAMPs) that activate DCs directly through the ligation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs). In addition, pathogens activate DCs indirectly, through factors that these pathogens induce by activating neighbouring cells in the infected tissue by the same PAMP–PRR principle. Certain pathogens can evade adaptive immunity by binding to receptors that initiate negative signals, which results in the inhibition of DC maturation and/or their expression of T-cell inhibitory molecules, both resulting in the development of anergic or regulatory T cells. In contrast to the original belief, DCs are essentially flexible and can adopt mature T helper 1 (T H 1)-, (T H 2)- or regulatory T-cell-promoting phenotypes, instructed by the priming signals from microbial and tissue-derived factors. PAMPs and tissue factors can be classified as type 1, type 2 and regulatory type, that programme (polarize) immature DCs to become mature effector DCs that selectively express T-cell-polarizing signals that promote the development of T H 1, T H 2 or regulatory T cells, respectively. Although most TLRs mediate the polarization of T H 1-cell-inducing DCs with variable efficacy, the PRRs that mediate T H 2-cell-inducing DCs remain ill-defined. In addition, some PRRs, including TLR2, can mediate negative signals and promote the development of regulatory DCs. DCs are heterogeneous and might differ in their ability to recognize PAMPs. In addition, some DC subsets have a fixed capacity to induce the development of regulatory T cells. The significance of the DC heterogeneity and the fixed T-cell-polarizing capacity remains to be established. Dendritic cells (DCs) are central in the orchestration of the various forms of immunity and tolerance. Their immunoregulatory role mainly relies on the ligation of specific receptors that initiate and modulate DC maturation resulting in the development of functionally different effector DC subsets that selectively promote T helper 1 (T H 1)-, T H 2- or regulatory T-cell res