Persistent loss of IL-27 responsiveness in CD8+ memory T cells abrogates IL-10 expression in a recall response

CD8+ T cells are central to the eradication of intracellular pathogens, but they can also act to limit inflammation and immunopathology. During primary respiratory viral infection CD8+ effector T cells release the immunosuppressive cytokine IL-10, which is essential for host survival. Here we report that CD8+ T-cell–derived IL-10 is absent in a recall response. We show in mice that the lack of IL-10 is due to a persistent loss of IL-27 responsiveness in CD8+ memory T cells, caused by down-regulation of the common cytokine receptor, glycoprotein 130. CD8+ memory T cells secreted less IL-10 when activated in the presence of IL-27 than did naïve controls, and retroviral expression of glycoprotein 130 restored IL-10 and reduced IFN-γ production upon restimulation. We demonstrate that human CD8+ memory cells are also characterized by impaired IL-27 responsiveness. Our data suggest that CD8+ T-cell activation involves a persistent loss of specific cytokine receptors that determines the functional potential of these cells during rechallenge infection

Specific Lipids Supply Critical Negative Spontaneous Curvature—An Essential Component of Native Ca2+-Triggered Membrane Fusion

The Ca2+-triggered merger of two apposed membranes is the defining step of regulated exocytosis. CHOL is required at critical levels in secretory vesicle membranes to enable efficient, native membrane fusion: CHOL-sphingomyelin enriched microdomains organize the site and regulate fusion efficiency, and CHOL directly supports the capacity for membrane merger by virtue of its negative spontaneous curvature. Specific, structurally dissimilar lipids substitute for CHOL in supporting the ability of vesicles to fuse: diacylglycerol, αT, and phosphatidylethanolamine support triggered fusion in CHOL-depleted vesicles, and this correlates quantitatively with the amount of curvature each imparts to the membrane. Lipids of lesser negative curvature than cholesterol do not support fusion. The fundamental mechanism of regulated bilayer merger requires not only a defined amount of membrane-negative curvature, but this curvature must be provided by molecules having a specific, critical spontaneous curvature. Such a local lipid composition is energetically favorable, ensuring the necessary “spontaneous” lipid rearrangements that must occur during native membrane fusion—Ca2+-triggered fusion pore formation and expansion. Thus, different fusion sites or vesicle types can use specific alternate lipidic components, or combinations thereof, to facilitate and modulate the fusion pore