The T cell receptor resides in ordered plasma membrane nanodomains that aggregate upon patching of the receptor

Abstract

Two related models for T cell signalling initiation suggest either that T cell receptor (TCR) engagement leads to its recruitment to ordered membrane domains, often referred to as lipid rafts, where signalling molecules are enriched or that ordered TCR-containing membrane nanodomains coalesce upon TCR engagement. That ordered domains form upon TCR engagement, as they do upon lipid raft marker patching, has not been considered. The target of this study was to differentiate between those three options. Plasma membrane order was followed in live T cells at 37 °C using laurdan to report on lipid packing. Patching of the TCR that elicits a signalling response resulted in aggregation, not formation, of ordered plasma membrane domains in both Jurkat and primary T cells. The TCR colocalised with actin filaments at the plasma membrane in unstimulated Jurkat T cells, consistent with it being localised to ordered membrane domains. The colocalisation was most prominent in cells in G1 phase when the cells are ready to commit to proliferation. At other cell cycle phases the TCR was mainly found at perinuclear membranes. Our study suggests that the TCR resides in ordered plasma membrane domains that are linked to actin filaments and aggregate upon TCR engagement.

Microdomains, Inflammation, and Atherosclerosis

“…69, 70 The importance of these domains for immune cell activation and polarization has been widely studied in many different systems using the addition of β-cyclodextrin or squalene directly in vivo or in vitro to deplete or replete membrane cholesterol. 71–74 In particular, the role of lipid rafts in bone marrow stem cell hierarchy is consistent with these structures acting as the master regulators of hematopoietic stem cell retention and quiescence in bone marrow niches, as well as serving a role in regulating their mobilization and homing. 75, 76 Therefore, how the cell regulates lipid raft formation, composition, and disassembly are of great interest and could be utilized for therapeutic intervention in cardiovascular disease.…”

Urate crystals directly activate the T-cell receptor complex and induce T-cell proliferation

“…The rationale behind this attempt was based on the fact that the TCR-complex and other co-receptors lie within lipid rafts in cell membrane (13,14), and, at least in dendritic cells, urate crystals by sequestering lipid rafts they bring together ITAM containing receptors resulting in their activation and the initiation of intracellular signal transduction events (12). This potential of urate crystals to activate cells through nonspecific clustering of cell membrane receptors due to lipid raft sequestration has been confirmed in macrophages as well, in which they induce NALP3 activation (20).…”

“…In case of direct T-cell activation by urate crystals, the aforementioned model applied in dendritic cells becomes quite attractive. If urate crystals are able to aggregate lipid rafts in general, then they could cloister many TCR-complexes and co-receptors together, considering the fluidity of the membrane and the abundance of TCR-complexes and co-receptors in T-cells' lipid rafts (13,14). Such a sequestration of receptors would eventually lead to T-cell activation.…”

Impact of lipid rafts on theT-cell-receptor and peptide-major-histocompatibility-complex interactions under different measurement conditions

“…According to the experimental observations, lipid rafts are modeled to represent 30% of the T cell membrane; 50% of total TCRs are set to reside in raft regions at equilibrium [4,22,37]. Depending on the detection methods, the lipid rafts in the T-cell membrane vary widely in size.…”

“…Recently, the implications * songf@lnm.imech.ac.cn of lipid rafts in T-cell activation and thymocyte selection have been investigated [4,[13][14][15][16][17][18][19][20][21][22][23]. Lipid rafts, cholesteroland sphingolipid-enriched membrane microdomains, exist as distinct liquid-ordered phases that float freely as stable entities in the liquid-disordered matrix of the plasma membrane.…”