Abstract
Many innate immune receptors function collaboratively to detect and elicit immune responses to pathogens, but the physical mechanisms that govern the interaction and signaling crosstalk between the receptors are unclear. In this study, we report that the signaling crosstalk between Fc gamma receptor (FcγR) and Toll-like receptor (TLR)2/1 can be overall synergistic or inhibitory depending on the spatial proximity between the receptor pair on phagosome membranes. Using a geometric manipulation strategy, we physically altered the spatial distribution of FcγR and TLR2 on single phagosomes. We demonstrate that the signaling synergy between FcγR and TLR2/1 depends on the proximity of the receptors and decreases as spatial separation between them increases. However, the inhibitory effect from FcγRIIb on TLR2-dependent signaling is always present and independent of receptor proximity. The overall cell responses are an integration from these two mechanisms. This study presents quantitative evidence that the nanoscale proximity between FcγR and TLR2 functions as a key regulatory mechanism in their signaling crosstalk.
Highlights
Innate immune cells use a variety of receptors to recognize invading pathogens and elicit appropriate immune responses
By using fluorescently labeled immunoglobulin G (IgG) and streptavidin, we confirmed that IgG and Pam3CSK4 were selectively functionalized on opposite sides of Janus IgG/Pam3 (jIPam) particles with no cross-contamination (Fig. 1b)
We showed that the FcγRs and TLR2/1 receptors on phagosomes encapsulating such engineered particles are spatially re-organized to follow the ligand patterns on the surfaces of the particles
Summary
Innate immune cells use a variety of receptors to recognize invading pathogens and elicit appropriate immune responses. We present new evidence supporting a vital role for spatial organization in FcγR and TLR2/1 crosstalk in macrophage cells These two types of receptors recognize different microbial ligands. FcγRs, including FcγRIIa, synergize with TLR2 in triggering proinflammatory cytokine secretion in macrophages This is known because the knockout or blockade of either type of receptors has been shown to cause a reduction in immune cell r esponse[37,38,39]. Binding of FcγRIIa to anti-FcγRII antibody fragments inhibits TLR4-triggered cytokine responses in mouse macrophages[41] Taken together, such studies clearly demonstrate the complex nature of the cross-regulation between FcγRs and TLRs in immune responses. The physical mechanisms governing the differential effects of FcγRs in receptor signaling crosstalk remain elusive
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