Another study showed that prestimulation of ITAM-coupled receptors and integrins can inhibit TLR responses indirectly through induction of inhibitors such as IL-10, STAT3, SOCS3, ABIN-3, and A20 69. The inhibitory capacity of receptors previously believed to only activate cells, emphasizes the complex signaling networks and cross-talk

in signal transduction pathways, and will contribute to a tightly balanced immune response. Coevolution of interacting species drives molecular evolution through continual natural selection for adaptation and counter adaptation. Hence, pathogens coevolving with humans have developed multiple mechanisms to evade immune recognition. MI-503 in vitro A pathogen that encodes a functional Tigecycline ligand for a phagocyte inhibitory receptor could enhance survival

by suppressing effector functions such as phagocytosis, ROS, and cytokine production. It has been shown that Staphylococcus aureus binds specifically to PIR-B, a suppressor of TLR-mediated inflammatory responses, and PIR-B-deficient macrophages display enhanced inflammatory responses to S. aureus90. The specific bacterial protein that binds to PIR-B remains to be determined. Bacterially encoded ligands have also been found for Siglec-5 and Siglec-9 30, 91. The group B Streptococcus cell wall-anchored β protein specifically binds Siglec-5, and it was shown that Siglec-5 activation through Phosphoglycerate kinase β protein results in less phagocytosis, less oxidative burst, fewer neutrophil extracellular traps (NETs 92) and reduced IL-8 production in neutrophils 91. Other examples of bacterially encoded proteins that act as a functional ligand for inhibitory receptors include interaction of surface protein A1 on Moraxella catarrhalis or opacity-associated proteins on Neisseria meningitidis with

CEACAM1 93. Evolutionary selection of pathogens that produce ligands for inhibitory receptors indicates that it can lead to an evolutionary advantage, which in turn underlines the importance of inhibitory receptors as regulators of phagocyte cell function. Considering the number of inhibitory receptors on phagocytes, it is likely that many more bacterially encoded ligands for inhibitory receptors will be discovered. Interestingly, activating family members have been described for many inhibitory receptors and often a cell will express both inhibitory and activating members of the same receptor 94. These so-called paired receptors include Siglecs 95, CD200R 96, PIR 97, SIRP 97, KIR, and Ly49 94. In the light of the discussion above, it is fascinating to speculate that the evolution of these activating counterparts is driven by the continuous battle between pathogens and host. An important study by Abi-Rached and Parham demonstrate that activating KIR members are derived from inhibitory KIRs 98.