Innate immune receptor clustering and its role in immune regulation

Abstract

The discovery of receptor clustering in the activation of adaptive immune cells has revolutionized our understanding of the physical basis of immune signal transduction. In contrast to the extensive studies of adaptive immune cells, particularly T cells, there is a lesser, but emerging, recognition that the formation of receptor clusters is also a key regulatory mechanism in host–pathogen interactions. Many kinds of innate immune receptors have been found to assemble into nano- or micro-sized domains on the surfaces of cells. The clusters formed between diverse categories of innate immune receptors function as a multi-component apparatus for pathogen detection and immune response regulation. Here, we highlight these pioneering efforts and the outstanding questions that remain to be answered regarding this largely under-explored research topic. We provide a critical analysis of the current literature on the clustering of innate immune receptors. Our emphasis is on studies that draw connections between the phenomenon of receptor clustering and its functional role in innate immune regulation.

Significance of Receptor Mobility in Multivalent Binding on Lipid Membranes

“…Together, this range of studies suggests that mobility of receptors embedded in the bilayer is of significance in many signalling cellular pathways involving multivalent processes, e.g., formation of immune synapses. [18] Clustering and cross‐linking of receptors often requires them to be mobile in the bilayer and can be strongly correlated with their activity. [ 30 , 50 , 51 , 52 , 53 , 54 ] This mobility, however, plays a bigger role at low receptor concentrations.…”

“…[ 16 , 17 ] The mobility of the membrane thus plays a significant role in fulfilling the spacing requirements of the embedded receptors, in processes as crucial as, e.g., the activation of adaptive immune cells, where receptor clustering was identified as a key regulatory mechanism. [18] Understanding its role will deepen our knowledge of the natural binding processes and guide the design of novel multivalent ligands, relying not on statistical “brute force”, but rather a more sophisticated, tailored approach. [19] …”

Recent advances in engineering nanotopographic substrates for cell studies

“…The clustering of transmembrane receptors is common among different types of immune cells ( Dustin and Groves, 2012 ; Li and Yu, 2021 ). T cell receptors (TCRs) on resting T cells can be found as monomers and as cholesterol- and sphingomyelin-stabilized nanoclusters (<10%) containing 2–30 TCRs each ( Molnár et al, 2012 ).…”

Multimericity Amplifies the Synergy of BCR and TLR4 for B Cell Activation and Antibody Class Switching

“…In macrophages and DCs, the PRR dectin-1, which detects fungal beta-glucans ( 42 ), was activated at significantly higher levels by multimeric, particulate ligands compared to their monomeric, soluble forms. Likewise, while some TLRs can detect individual monomeric ligands, they are activated to higher levels by forming nanoclusters of the same kind (homotypic) or different kinds (heterotypic) of receptors ( 43 , 44 ). The cellular basis for such heightened responses is considered to be the formation of particular lipid rafts ( 44 ), recruitment and stabilization of downstream signaling mediators ( 43 , 44 ), endocytosis or phagocytosis and its signaling ( 45 ), cytoplasmic phase separation into receptor and mediator rich liquid-like condensates ( 46 ), or combinations of the above.…”