No abstract

Humans and animals must often discriminate between complex natural sounds in the presence of competing sounds (maskers). Although the auditory cortex is thought to be important in this task, the impact of maskers on cortical discrimination remains poorly understood. We examined neural responses in zebra finch (Taeniopygia guttata) field L (homologous to primary auditory cortex) to target birdsongs that were embedded in three different maskers (broadband noise, modulated noise and birdsong chorus). We found two distinct forms of interference in the neural responses: the addition of spurious spikes occurring primarily during the silent gaps between song syllables and the suppression of informative spikes occurring primarily during the syllables. Both effects systematically degraded neural discrimination as the target intensity decreased relative to that of the masker. The behavioral performance of songbirds degraded in a parallel manner. Our results identify neural interference that could explain the perceptual interference at the heart of the cocktail party problem.

HLA class II-restricted regulatory T cell (Treg) epitopes in IgG (also called “Tregitopes”) have been reported to suppress immune responses to coadministered antigens by stimulating the expansion of natural Tregs (nTregs). Here we evaluate their impact on human immune responses to islet cell antigens ex vivo and on the modulation of type 1 diabetes (T1D) in a murine model in vivo. Co-administration of Tregitopes and T1D antigens delayed development of hyperglycemia and reduced the incidence of diabetes in NOD mice. Suppression of diabetes could be observed even following onset of disease. To measure the impact of Tregitope treatment on T cell responses, we evaluated the effect of Tregitope treatment in DO11.10 mice. Upregulation of FoxP3 in KJ1-26-stained OVA-specific CD4+ T cells was observed following treatment of DO11.10 mice with Tregitopes, along with reductions in anti-OVA Ig and T effector responses. In ex vivo studies of human T cells, peripheral blood mononuclear cells' (PBMC) responses to GAD65 epitopes in the presence and absence of Tregitope were variable. Suppression of immune responses to GAD65 epitopes ex vivo by Tregitope appeared to be more effective in assays using PBMC from a newly diagnosed diabetic subject than for other more established diabetic subjects, and correlation of the degree of suppression with predicted HLA restriction of the Tregitopes was confirmed. Implementation of these defined regulatory T cell epitopes for therapy of T1D and other autoimmune diseases may lead to a paradigm shift in disease management.