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

The interactions between T-cell receptor (TCR) and peptide-major-histocompatibility complex (pMHC), which enable T-cell development and initiate adaptive immune responses, have been intensively studied. However, a central issue of how lipid rafts affect the TCR-pMHC interactions remains unclear. Here, by using a statistical-mechanical membrane model, we show that the binding affinity of TCR and pMHC anchored on two apposing cell membranes is significantly enhanced because of the lipid raft-induced signaling protein aggregation. This finding may provide an alternative insight into the mechanism of T-cell activation triggered by very low densities of pMHC. In the case of cell-substrate adhesion, our results indicate that the loss of lateral mobility of the proteins on the solid substrate leads to the inhibitory effect of lipid rafts on TCR-pMHC interactions. Our findings help to understand why different experimental methods for measuring the impact of lipid rafts on the receptor-ligand interactions have led to contradictory conclusions.

Figure 1

Illustration of antigen recognition via TCR-pMHC interactions in the presence of lipid rafts.

Figure 2

(a) Snapshots of the spatial distribution of signaling proteins and lipid rafts in the T-cell and APC membranes at equilibrium. (b) Time evolution of TCR-pMHC complex fraction for three values of ρ. The number of permanently captured proteins in each lipid raft is 1. Each lipid raft here has a fixed area of $50\times 50\mathrm{n}{\mathrm{m}}^2$. The parameter values used in the simulation are shown in Table 1.

Figure 3

Area concentration of pMHC molecules in lipid rafts and TCR-pMHC complex fraction as a function of the parameters ρ and ϕ for raft affinity of $\mathrm{\Delta }{U}_{\mathrm{affinity}}=–3k_{B}T$. The parameter values used in the simulation are shown in Table 1.

Figure 4

(a) Snapshots of the equilibrium spatial distribution of signaling proteins and lipid rafts for protein number in each raft equaling 5. (b) Membrane fraction $P_b$ within binding range as a function of rescaled effective potential depth $u$ for lipid rafts loaded with different numbers of signaling proteins denoted by $N_{\mathrm{pro}}$. Here, the dependence of $P_b$ on $u$ is obtained by varying the number of signaling proteins in each membrane. For simplicity, the number of TCRs is set to be the same as that of pMHC in that case. The raft number is determined by the ratio of protein number and $N_{\mathrm{pro}}$. The parameter values used in the simulation are shown in Table 1.

Figure 5

(a) Snapshots of the equilibrium spatial distribution of TCRs and lipid rafts for raft affinity $\mathrm{\Delta }{U}_{\mathrm{affinity}}\to +\infty$ and raft making up 35% of the T-cell membrane with different side lengths. (b) Effect of the exclusion of signaling protein from lipid rafts on the complex fraction for different raft sizes. (c) Pair distribution function $g$(r) as a function of the distance r for raft making up 75% of the membranes with raft side lengths ranging from 10 to 90 nm. The raft size and area are set to be the same in T-cell and APC membranes in this figure. The parameter values used in the simulation are shown in Table 1.

Figure 6

Influence of thermal membrane fluctuations on the positive contribution made by the aggregation effect of signaling proteins inside and outside lipid rafts. Φ is the ratio of the number of TCR-pMHC complexes in the presence and absence of lipid rafts. In case I, the equilibrium protein number in each raft is 5. In case II, lipid rafts make up 75% of the T-cell and APC membranes with raft affinity $\mathrm{\Delta }{U}_{\mathrm{affinity}}\to +\infty$. The side length of the lipid rafts is 50 nm in the two cases. The parameter values used in the simulation are shown in Table 1.

Figure 7

(a) TCR-pMHC complex fraction as a function of the raft area ratio and raft size with parameters derived from experimental measurements. The olive line shows the values obtained in the absence of lipid rafts in the APC membrane. (b) Snapshots of the equilibrium spatial distribution of pMHCs and lipid rafts for three different raft areas marked with the numbers ①, ②, ③ corresponding to those in (a). The raft affinity is set as $\mathrm{\Delta }{U}_{\mathrm{affinity}}\to -\infty$ at the beginning of simulations. Here, the pMHCs are set to occupy at most 20% of the total raft regions due to the finite protein-carrying capability. The raft affinity for pMHCs in nonraft regions becomes $\mathrm{\Delta }{U}_{\mathrm{affinity}}\to +\infty$, and the pMHCs will not be allowed to enter into these microdomains if the protein-carrying capability of the total raft regions is reached. As a result, the equilibrium area concentration of pMHC in the total raft regions has fixed at $0.2/a^2$ before the raft area is increased to a value large enough to be capable of exactly adsorbing all the pMHC molecules ($①\to ②$). However, with further increase in raft area, the equilibrium area concentration of pMHC within the total raft regions decreases gradually ($②\to ③$). (c) Time sequence of spatial distribution of signaling proteins and lipid rafts (②, top view). The lipid rafts carrying TCRs on T cell at equilibrium incline to be located in the membrane apposing the lipid rafts carrying pMHCs on APC. The snapshots are taken at ${10}^3,{10}^5,{10}^6$, and ${10}^7$ MC steps. The final snapshot represents an equilibrium state.

Figure 8

(a) The extent to which lipid rafts facilitate the TCR-pMHC bond formation as a function of raft size for different amounts of pMHC in lipid rafts. According to the experimental results, lipid rafts cover 10% of the APC surface [51]. The parameter values used in the simulation are shown in Table 1. (b) Snapshots of the equilibrium spatial distribution of pMHCs and lipid rafts for three concentrations of pMHCs in these microdomains. The pMHC molecules in nonraft regions are no longer allowed to enter into lipid rafts when the specified pMHC-carrying capability of the total raft regions is reached.

Figure 9

(a) TCR-pMHC complex fraction as a function of the raft area ratio under five different attractive interaction values $U_{\alpha \alpha }$. The olive line shows the values obtained in the absence of lipid rafts in the APC membrane. (b) Time sequence of spatial distribution of dynamic rafts experiencing attractive interaction $U_{\alpha \alpha }={\left(U_{\alpha \alpha }\right)}_c$ for different raft coverage areas. The snapshots are taken at ${10}^3,{10}^5,{10}^6$, and $5\times {10}^7$ MC steps. The final snapshots represent the equilibrium state. (c) The average size of lipid rafts in the APC membrane as a function of the raft area ratio under five different attractive interaction values $U_{\alpha \alpha }$.

Figure 10

(a) TCR-pMHC complex fraction as a function of the raft area ratio and raft size for raft affinity of $\mathrm{\Delta }{U}_{\mathrm{affinity}}=–3k_{B}T$. (b) The concentration of pMHC molecules in raft regions as a function of the raft area ratio and size in the absence $(U_{\mathrm{binding}}=0)$ and presence $(U_{\mathrm{binding}}=5.0k_{B}T)$ of TCR-pMHC interactions. The parameter values used in the simulation are shown in Table 1.

Figure 11

The influence of lipid rafts on the TCR-pMHC interaction for the cell-substrate model constituted of a flat TCR-containing lipid bilayer supported on a solid substrate. The simulation results in (a,b) are from the static and dynamic raft models, respectively. The olive line shows the values obtained in the absence of lipid rafts in the APC membrane. The parameter values used in the simulation are shown in Table 1.

Figure 12

Simulation results from the static (a) and dynamic (b) raft models showing the negative regulation of lipid rafts on the TCR-pMHC interactions for the case of immobilized TCRs coated on the substrate. As in Figs. 7 and 9, the signaling proteins can occupy no more than 20% of the total raft regions. (c) Detrimental effect of lipid rafts on the complex formation for cell-surface pMHCs and immobilized TCRs in the case where raft affinity $\mathrm{\Delta }{U}_{\mathrm{affinity}}=–3k_{B}T$. (d) Complex fraction with respect to immobilized protein number and raft size for all pMHCs residing in these microdomains. The area concentration of pMHC molecules in the total raft regions is $0.2/a^2$. The results in subfigures (c,d) are obtained from the static raft model. The olive line shows the values obtained in the absence of lipid rafts in the APC membrane. The parameter values used in these panels are shown in Table 1.