While membrane models now include the heterogeneous distribution of lipids, the impact of membrane charges on regulating the association of proteins with the plasma membrane is often overlooked. Charged lipids are asymmetrically distributed between the two leaflets of the plasma membrane, resulting in the inner leaflet being negatively charged and a surface potential that attracts and binds positively charged ions, proteins and peptide motifs. These interactions not only create a transmembrane potential, they can also facilitate the formation of charged membrane domains. Here we reference fields outside of immunology in which consequences of membrane charge are better characterised to highlight important mechanisms. We then focus on T cell receptor (TCR) signalling, reviewing the evidence that membrane charges and membrane-associate calcium regulate phosphorylation of the TCR-CD3 complex and discuss how the immunological synapse exhibits distinct patterns of membrane charge distribution. We propose that charged lipids, ions in solution and transient protein interactions form a dynamic equilibrium during T cell activation.

Several S100 Ca²⁺-binding proteins undergo various post-translational modifications that may alter their intracellular and extracellular functions. S100A8 and S100A9, two members of this family, are particularly susceptible to oxidative modification. These proteins, abundantly expressed in neutrophils and activated macrophages, are associated with acute and chronic inflammatory conditions, including microbial infections, cystic fibrosis, rheumatoid arthritis, and atherosclerosis. They have diverse intracellular roles including NADPH oxidase activation and arachidonic acid transport and can be secreted via a Golgi-independent pathway to exert extracellular functions. Many pro-inflammatory functions have been described for S100A8 and S100A9, but they are also implicated in anti-inflammatory roles in wound-healing and protection against excessive oxidative tissue damage, the latter as a result of their exquisite capacity to scavenge oxidants. Similarly, their genes are induced by proinflammatory (LPS and TNF-α) stimuli, but induction is IL-10-dependent, and anti-inflammatory glucocorticoids induce or amplify expression. S100A8 and S100A9 were described recently as damage-associated molecular pattern molecules, which provide a novel, conceptual framework for understanding their functions. However, because of this designation, recent reviews focus solely on their pro-inflammatory functions. Here, we summarize the mounting evidence from functional and gene regulation studies that these proteins may also play protective roles. This review offers an explanation for the disparate, functional roles of S100A8 and S100A9 based on emerging data that post-translational, oxidative modifications may act as a regulatory switch.