Dendritic Cells as Sensors of Infection

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There are many different signals that induce DC activation, from PAMPs to intracellular self-components. Why so much redundancy? It may be argued that all these signals have in common an evolutionary link to infection. In the race against a replicating pathogen, early recognition of infection provides a competitive advantage. Primitive immune systems presumably learned to recognize any signal that correlated with infection, even if only weakly. The reverse of the coin is that some signals may now also activate DC to become immunogenic in the absence of infection. Does this matter? Over time, tolerogenic APC and/or tissues can purge the peripheral repertoire of most self-reactive T cells (see Matzinger, 1994xMatzinger, P. Annu. Rev. Immunol. 1994; 12: 991–1045Crossref | PubMedSee all ReferencesMatzinger, 1994, for a discussion). Thus, provided it does not become so prevalent as to prevent peripheral tolerance, it is better to err on the side of excess APC activation and cry wolf (or, in this case, pathogen) even when there is none around. In this context, it is worth remembering that if innate recognition of infection was absolute, DC could be endowed with destructive function and replace lymphocytes. DC do not have the exquisite antigen discrimination ability conferred by clonally distributed receptors and can only act as advisors, providing T cells with information of evolutionary value. T cells are the ultimate decision makers and can follow or ignore this advice based on their history of antigen exposure.Many questions remain to be answered in the field. For example, why do we recognize PAMPs but are tolerant of commensal bacteria in gut and skin? Can we correlate particular forms of DC activation with given categories of stimuli? What are the consequences of each form of DC activation for the immune response? Can our understanding of signals for DC activation be used to design better adjuvants for vaccination and immunotherapy? These and other questions are likely to keep DC in the limelight for many years to come, which is perhaps appropriate for a star-shaped APC.