T cells recognize protein antigens as short peptides processed and displayed by antigen-presenting cells. However, the mechanism of peptide selection is incompletely understood, and, consequently, the differences in the immunogenicity of protein antigens remain largely unpredictable and difficult to manipulate. In this paper we show that the susceptibility of protein antigens to lysosomal proteolysis plays an important role in determining immunogenicity in vivo. We compared the immunogenicity of proteins with the same sequence (same T cell epitopes) and structure (same B cell epitopes) but with different susceptibilities to lysosomal proteolysis. After immunizing mice with each of the proteins adsorbed onto aluminum hydroxide as adjuvant, we measured serum IgG responses as a physiological measure of the antigen's ability to be presented on major histocompatibility complex class II molecules and to prime CD4+ T cells in vivo. For two unrelated model antigens (RNase and horseradish peroxidase), we found that only the less digestible forms were immunogenic, inducing far more efficient T cell priming and antibody responses. These findings suggest that stability to lysosomal proteolysis may be an important factor in determining immunogenicity, with potential implications for vaccine design.
We have generated a mouse model of this condition by replacing the wild type gene with one encoding Kcnt1 R455H , a cytoplasmic c-terminal mutation homologous to a human R474H variant that results in EIMFS. We compared behavior patterns and seizure activity in these mice with those of wild type mice and Kcnt1 −/− mice. Complete loss of Kcnt1 produced deficits in open field behavior and motor skill learning. Although their thresholds for electrically and chemically induced seizures were similar to those of wild type animals, Kcnt1 −/− mice were significantly protected from death after maximum electroshock-induced seizures. In contrast, homozygous Kcnt1 R455H/R455H mice were embryonic lethal. Video-EEG monitoring of heterozygous Kcnt1 +/R455H animals revealed persistent interictal spikes, spontaneous seizures and a substantially decreased threshold for pentylenetetrazoleinduced seizures. Surprisingly, Kcnt1 +/R455H mice were not impaired in tasks of exploratory behavior or procedural motor learning. These findings provide an animal model for EIMFS and suggest that Slack channels are required for the development of procedural learning and of pathways that link cortical seizures to other regions required for animal survival.Sodium influx into neurons through voltage-dependent sodium channels and through glutamate receptors during repetitive firing in neurons leads to the activation of Na + -activated K + currents, termed K Na currents 1 . Many K Na currents are mediated by two related potassium channel subunits 2 . Like many ion channels, these two subunits have had multiple names over time, and the names used here are Slack (also called K Na 1.1 or Slo2.2 and encoded by the KCNT1 gene) and Slick (K Na 1.2, Slo2.1, encoded by the KCNT2 gene) 3,4 . The Slack (Sequence Like A Calcium-activated K + Channel) subunit is widely expressed in the mammalian nervous system 5 . Rapid activation of K Na currents contributes to action potential repolarization and shapes synaptic potentials, while slower activation produces adaptation of firing rates during sustained neuronal stimulation and to afterhyperpolarizations that follow such stimulation 6 , K Na currents also regulate the temporal accuracy of action potentials in response to high-frequency stimulation 7 .Slack channels resemble K v channels in their transmembrane topology, with six hydrophobic transmembrane domains 8 . The large cytoplasmic C-terminal domain of the Slack subunit, however, shares similarities with the BK potassium channel 9 and contains two RCK (regulator of the conductance of K) domains. In addition to having a putative Na + sensing domain 10 , the C-terminus is required for the interactions between the Slack protein and cytoplasmic signaling molecules such as Phactr-1 and the Fragile X Mental Retardation Protein (FMRP) 11,12 .
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