Cooperative binding of T cell receptor and CD4 to peptide-MHC enhances antigen sensitivity.

Antigen recognition by the T cell receptor (TCR) of CD4 T cells can be greatly enhanced by the coreceptor CD4. Yet, understanding of the molecular mechanism is hindered by the ultra-low affinity of CD4 binding to class-II peptide-major histocompatibility complexes (pMHC). Here we show, using two-dimensional (2D) mechanical-based assays, that the affinity of CD4-pMHC interaction is 3-4 logs lower than that of cognate TCR-pMHC interactions, and it is more susceptible to increased dissociation by forces (slip bond).

Two-Dimensional Analysis of Cross-Junctional Molecular Interaction by Force Probes.

Upon engagement with a specific ligand, a cell surface receptor transduces intracellular signals to activate various cellular functions. This chapter describes a set of biomechanical methods for analyzing the characteristics of cross-junctional receptor-ligand interactions at the surface of living cells. These methods combine the characterization of kinetics of receptor-ligand binding with real-time imaging of intracellular calcium fluxes, which allow researchers to assess how the signal initiated from single receptor-ligand engagement is transduced across the cell membrane.

Endothelial and leukocyte heparan sulfates regulate the development of allergen-induced airway remodeling in a mouse model.

Heparan sulfate (HS) proteoglycans (HSPGs) participate in several aspects of inflammation because of their ability to bind to growth factors, chemokines, interleukins and extracellular matrix proteins as well as promote inflammatory cell trafficking and migration. We investigated whether HSPGs play a role in the development of airway remodeling during chronic allergic asthma using mice deficient in endothelial- and leukocyte-expressed N-deacetylase/N-sulfotransferase-1 (Ndst1), an enzyme involved in modification reactions during HS biosynthesis. Ndst1-deficient and wild-type (WT) mice exposed to repetitive allergen (ovalbumin [OVA]) challenge were evaluated for the development of airway remodeling.