There are several other candidate DNA sensors, but less is known about the mechanism of their recognition and signaling, or their in vivo activity. IFI16 (IFN-γ-inducible protein 16) is a PYHIN family member related to AIM2, but appears to function in DNA sensing and acts through STING, TBK1, and IRF3 rather than activating an inflammasome pathway. DDX41 (DEAD box polypeptide 41) is an RLR related to RIG-I and is a member of the DEAD-box family, but appears to signal through STING rather than MAVS. MRE11A (meitotic recombination 11 homolog a) can sense cytosolic double-stranded DNA to activate the STING pathway, but its role in innate immunity is currently unknown.
3-12 Activation of innate sensors in macrophages and dendritic far-reaching effects on the immune response.
Besides activating effector functions and cytokine production, another outcome of the activation of innate sensing pathways is the induction of co-stimulatory molecules on tissue dendritic cells and macrophages (see Section 1-15). We will describe these in more detail later in the book, but mention them now because they provide an important link between innate and adaptive immune responses. Two important co-stimulatory molecules are the cell-surface proteins B7.1 (CD80) and B7.2 (CD86), which are induced on macrophages and tissue dendritic cells by innate sensors such as TLRs in response to pathogen recognition (Fig. 3.23). B7.1 and B7.2 are recognized by specific co-stimulatory receptors expressed by cells of the adaptive immune response, particularly CD4 T cells, and their activation by B7 is an important step in activating adaptive immune responses.
Substances such as LPS that induce co-stimulatory activity have been used for years in mixtures that are co-injected with protein antigens to enhance their immunogenicity. These substances are known as adjuvants (see Appendix I, Section A-1), and it was found empirically that the best adjuvants contain microbial components that induce macrophages and tissue dendritic cells to express co-stimulatory molecules and cytokines. As we shall see in Chapters 9 and 11, the cytokines produced in response to infections influence the functional character of the adaptive immune response that develops. In this way the ability of the innate immune system to discriminate among different types of pathogens is used by the organism to ensure an appropriate module of adaptive immune response.
3-13 Toll signaling in Drosophila is downstream of a distinct set of pathogen-recognition molecules.