Recycling and LFA‐1‐dependent trafficking of ICAM‐1 to the immunological synapse

Abstract

Little is known about how adhesion molecules on APCs accumulate at immunological synapses. We show here that ICAM-1 on APCs is continuously internalized and rapidly recycled back to the interface after antigen-priming T-cell contact. The internalization rate is high in APCs, including Raji B cells and dendritic cells, but low in endothelial cells. Internalization is significantly reduced by inhibitors of Na(+)/H(+) exchangers (NHEs), suggesting that members of the NHE-family regulate this process. Once internalized, ICAM-1 is co-localized with MHC class II in the polarized recycling compartment. Surprisingly, not only ICAM-1, but also MHC class II, is targeted to the immunological synapse through LFA-1-dependent adhesion. Cytosolic ICAM-1 is highly mobile and forms a tubular structure. Inhibitors of microtubule or actin polymerization can reduce ICAM-1 mobility, and thereby block accumulation at immunological synapses. Membrane ICAM-1 also moves to the T-cell contact zone, presumably through an active, cytoskeleton-dependent mechanism. Collectively, these results demonstrate that ICAM-1 can be transported to the immunological synapse through the recycling compartment. Furthermore, the high-affinity state of LFA-1 on T cells is critical to induce targeted movements of both ICAM-1 and MHC class II to the immunological synapse on APCs.

Regulation of T‐lymphocyte motility, adhesion and de‐adhesion by a cell surface mechanism directed by low density lipoprotein receptor‐related protein 1 and endogenous thrombospondin‐1

“…Dynamin has previously been shown to regulate T‐cell activation by controlling actin polymerization at the immunological synapse, pointing to the possibility that synapse formation also involves LRP1. This contention is supported by the fact that ICAM‐1, as shown here, activates the motogenic TSP‐1/LRP1 mechanism and is a key structure on antigen‐presenting cells involved in the formation of immunological synapses …”

“…This contention is supported by the fact that ICAM-1, as shown here, activates the motogenic TSP-1/LRP1 mechanism and is a key structure on antigen-presenting cells involved in the formation of immunological synapses. 47 The accessibility on the cell surface together with the fact that it regulates infiltrative properties of T cells makes the motogenic mechanism described here a potential therapeutic target for tailored treatment of inflammatory conditions. Accordingly, this mechanism has multiple antigenic structures for monoclonal antibodies or hybrid molecules to interfere with T-cell infiltration of various organs during the course of autoimmune and allergic disorders as well as during rejection of foreign transplants and graft-versus-host disease.…”

CD81 Controls Sustained T Cell Activation Signaling and Defines the Maturation Stages of Cognate Immunological Synapses

“…CD81 could mediate functional interactions between actin and CD3 or ICAM-1. On the IS APC side, continuous ICAM-1 recycling is controlled by LFA-1, actin, and microtubules (65). In B cells, CD81 microdomains alongside the actin cytoskeleton play a key role in regulating CD19 mobility and in organizing CD19 and B cell receptor (BCR) interactions that lead to BCR signaling (66).…”

Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives

“…The CAM pathway was shown to be different from classical vesicular uptake via clathrin- or caveolar-mediated endocytosis and, although related, also differed from macropinocytosis and phagocytosis in terms of signaling cascade, actin cytoskeleton reorganization, markers involved, and inhibitor sensitivity [436, 437]. Subsequent work by the Muro lab has provided further understanding on the regulation of this pathway, which has been validated by others in the context of ICAM-1-mediated pathogen invasion, membrane recycling at the immune synapse, and leukocyte extravasation via the transcellular route [438]. Upon engagement, ICAM-1 associates with the sodium-proton exchanger NHE1 at membrane regions enriched in cholesterol, sphingomyelin and gangliosides [436, 439].…”