Biomedical subjects

Jizhong Lou

Publications and source records attributed to Jizhong Lou.

8 recordsLinked to original sources

PubMed2025

Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity.

Therapeutically targeting pathogenic T cells in autoimmune diseases has been challenging. Although LAG-3, an inhibitory checkpoint receptor specifically expressed on activated T cells, is known to bind to major histocompatibility complex class II (MHC class II), we demonstrate that MHC class II interaction alone is insufficient for optimal LAG-3 function. Instead, LAG-3's spatial proximity to T cell receptor (TCR) but not CD4 co-receptor, facilitated by cognate peptide-MHC class II, is crucial in mediating CD4+ T cell suppression. Mechanistically, LAG-3 forms condensate with TCR signaling component CD3ε through its intracellular FSAL motif, disrupting CD3ε/lymphocyte-specific protein kinase (Lck) association. To exploit LAG-3's proximity to TCR and maximize LAG-3-dependent T cell suppression, we develop an Fc-attenuated LAG-3/TCR inhibitory bispecific antibody to bypass the requirement of cognate peptide-MHC class II. This approach allows for potent suppression of both CD4+ and CD8+ T cells and effectively alleviates autoimmune symptoms in mouse models. Our findings reveal an intricate and conditional checkpoint modulatory mechanism and highlight targeting of LAG-3/TCR cis-proximity for T cell-driven autoimmune diseases lacking effective and well-tolerated immunotherapies.

Animals↗

PubMed2006

A structure-based sliding-rebinding mechanism for catch bonds.

Catch bonds, whose lifetimes are prolonged by force, have been observed in selectin-ligand interactions and other systems. Several biophysical models have been proposed to explain this counterintuitive phenomenon, but none was based on the structure of the interacting molecules and the noncovalent interactions at the binding interface. Here we used molecular dynamics simulations to study changes in structure and atomic-level interactions during forced unbinding of P-selectin from P-selectin glycoprotein ligand-1. A mechanistic model for catch bonds was developed based on these observations. In the model, "catch" results from forced opening of an interdomain hinge that tilts the binding interface to allow two sides of the contact to slide against each other. Sliding promotes formation of new interactions and even rebinding to the original state, thereby slowing dissociation and prolonging bond lifetimes. Properties of this sliding-rebinding mechanism were explored using a pseudoatom representation and Monte Carlo simulations. The model has been supported by its ability to fit experimental data and can be related to previously proposed two-pathway models.

Computer Simulation↗

PubMed2006

Flow-enhanced adhesion regulated by a selectin interdomain hinge.

L-selectin requires a threshold shear to enable leukocytes to tether to and roll on vascular surfaces. Transport mechanisms govern flow-enhanced tethering, whereas force governs flow-enhanced rolling by prolonging the lifetimes of L-selectin-ligand complexes (catch bonds). Using selectin crystal structures, molecular dynamics simulations, site-directed mutagenesis, single-molecule force and kinetics experiments, Monte Carlo modeling, and flow chamber adhesion studies, we show that eliminating a hydrogen bond to increase the flexibility of an interdomain hinge in L-selectin reduced the shear threshold for adhesion via two mechanisms. One affects the on-rate by increasing tethering through greater rotational diffusion. The other affects the off-rate by strengthening rolling through augmented catch bonds with longer lifetimes at smaller forces. By forcing open the hinge angle, ligand may slide across its interface with L-selectin to promote rebinding, thereby providing a mechanism for catch bonds. Thus, allosteric changes remote from the ligand-binding interface regulate both bond formation and dissociation.

Cell Adhesion↗

PubMed2005

Midgap states in antiferromagnetic Heisenberg chains with a staggered field.

We study low-energy excitations in antiferromagnetic Heisenberg chains with a staggered field which splits the spectrum into a longitudinal and a transverse branch. Bound states are found to exist inside the field induced gap in both branches. They originate from the edge effects and are inherent to spin-chain materials. The sine-Gordon scaling h(2/3)(s)[log(h(s)](1/6) (h(s), the staggered field) provides an accurate description for the gap and midgap energies in the transverse branch for S=1/2 and the midgap energies in both branches for S=3/2 over a wide range of magnetic field; however, it can fit other low-energy excitations only at much lower field. Moreover, the integer-spin S=1 chain displays scaling behavior that does not fit this scaling law. These results reveal intriguing features of magnetic excitations in spin-chain materials that deserve further investigation.

Journal Article↗

PubMed2005

Catch bonds: physical models, structural bases, biological function and rheological relevance.

Force can shorten the lifetimes of macromolecular complexes (e.g., receptor-ligand bonds) by accelerating their dissociation. Perhaps paradoxical at first glance, bond lifetimes can also be prolonged by force. This counterintuitive behavior was named catch bonds, which is in contrast to the ordinary slip bonds that describe the intuitive behavior of lifetimes being shortened by force. Fifteen years after their theoretical proposal, catch bonds have finally been observed. In this article we review recently published data that have demonstrated catch bonds in the selectin system and suggested catch bonds in other systems, the theoretical models for their explanations, possible structural bases, their relation to flow-enhanced adhesion, and the potential biorheological relevance.

Cell Adhesion↗

PubMed2004

Force history dependence of receptor-ligand dissociation.

Receptor-ligand bonds that mediate cell adhesion are often subjected to forces that regulate their dissociation via modulating off-rates. Off-rates control how long receptor-ligand bonds last and how much force they withstand. One should therefore be able to determine off-rates from either bond lifetime or unbinding force measurements. However, substantial discrepancies exist between the force dependence of off-rates derived from the two types of measurements even for the same interactions, e.g., selectins dissociating from their ligands, which mediate the tethering and rolling of leukocytes on vascular surfaces during inflammation and immune surveillance. We used atomic force microscopy to measure survival times of P-selectin dissociating from P-selectin glycoprotein ligand 1 or from an antibody in both bond lifetime and unbinding force experiments. By a new method of data analysis, we showed that the discrepancies resulted from the assumption that off-rates were functions of force only. The off-rates derived from forced dissociation data depended not only on force but also on the history of force application. This finding provides a new paradigm for understanding how force regulates receptor-ligand interactions.

Algorithms↗

PubMed2003

String order in half-integer-spin antiferromagnetic Heisenberg chains.

We derive the extended string order parameter O(S) for antiferromagnetic Heisenberg chains with half-integer spin S in the valence-bond-solid picture. We obtain the analytic power-law scaling of O(S) versus the chain length L and show that O(S) scales at an extremely slow pace that decreases rapidly with growing spin magnitude. Furthermore, accurate numerical calculations show that the power-law scaling sets in only when L exceeds a characteristic length scale l(S) which increases very fast with growing S. Consequently, a pseudo-long-range string order exists in half-integer-spin Heisenberg chains. The implications of this result and its relationship to other topological features such as the end-chain states are discussed.

Journal Article↗

PubMed2003

Nonlocal topological order in antiferromagnetic Heisenberg chains.

We demonstrate the existence of nonlocal topological (string) order in half-integer-spin antiferromagnetic Heisenberg chains on macroscopic scale on the basis of analytical scaling analysis and density matrix renormalization group calculations. Strong numerical evidence leads to a conjecture that chains with S = (2m-1)/2 and m (m = integers) belong to the same topological class defined by the topological angle theta/pi = 1/m that plays a role similar to the fictitious gauge field in the fractional quantum Hall effect.

Journal Article↗