Antigen presentation is a key rate-limiting step in the immune response. Dendritic cells (DC) are the most potent antigen-presenting cells for naive T cells, due to their high expression of MHC and co-stimulatory molecules, but little is known about the biochemical pathways that regulate this function. We here demonstrate that monocyte-derived mature DC can be infected with adenovirus at high efficiency (>95%) and that this procedure can be used to dissect out which pathways are essential for inducing DC antigen presentation to naive T cells. Using adenoviral transfer of the endogenous inhibitor of NF-kappaB, IkappaBalpha, we show that DC antigen presentation is NF-kappaB dependent. The mechanism for this is that NF-kappaB is essential for three aspects of antigen-presenting function: blocking NF-kappaB coordinately down-regulates HLA class II, co-stimulatory molecules like CD80, CD86 and CD40, and immuno-stimulatory cytokines like IL-12 and tumor necrosis factor-alpha. In contrast adhesion molecules are up-regulated after infection with the adenovirus transferring IkappaBalpha, indicating that NF-kappaB also regulates the duration of T cell-DC interaction. These results establish NF-kappaB as an effective target for blocking DC antigen presentation and inhibiting T cell-dependent immune responses, and this finding has potential implications for the development of therapeutic agents for use in allergy, autoimmunity and transplantation.

Happiness is a subjective experience that is an ultimate goal for humans. Psychological studies have shown that subjective happiness can be measured reliably and consists of emotional and cognitive components. However, the neural substrates of subjective happiness remain unclear. To investigate this issue, we used structural magnetic resonance imaging and questionnaires that assessed subjective happiness, the intensity of positive and negative emotional experiences, and purpose in life. We found a positive relationship between the subjective happiness score and gray matter volume in the right precuneus. Moreover, the same region showed an association with the combined positive and negative emotional intensity and purpose in life scores. Our findings suggest that the precuneus mediates subjective happiness by integrating the emotional and cognitive components of happiness.

Dendritic cells (DC) are the most potent antigen‐presenting cells for naive T cells, due to their high expression of MHC and costimulatory molecules, but relatively little is known about the biochemical pathways that regulate this function. We used the proteasome inhibitor N‐benzyloxycarbonyl‐Ile‐Glu(O‐tert‐butyl)‐Ala‐leucinal (PSI) to demonstrate that DC antigen presentation is NFκB dependent. As PSI is not a specific inhibitor of NFκB, we reproduced this finding using a very specific approach, namely adenoviral gene transfer of IκBα, the naturally occurring inhibitor of NFκB. The mechanism for this inhibition of DC antigen presentation involves at least three aspects of antigen presenting function: down‐regulation of HLA class II, down‐regulationof CD86, and inhibition of the immunostimulatory cytokines IL‐12 and TNF‐α. In the light of the marked down‐regulation of antigen‐presentation cell function, it was of interest to investigate what effects exposure to PSI‐treated DC might have on T cell function. It was found that immunological tolerance was induced, as challenge of T cells previously exposed to PSI‐treated DC, with normal DC from the same donor did not restore their response, despite the presence of viable T cells. There were also changes in T cell surface markers, with down‐regulation of CD3 and CD25 expression, and inhibition of the production of Th1 cytokines like IL‐2 and IFN‐γ. These results demonstrates that NFκB is an effective target for blocking DC antigen presentation and inhibiting T cell‐dependent immune responses, and this has implications for the development of therapeutic agents for use in multiple conditions, including transplantation, allergy and autoimmune diseases.

Previous electromyographic studies have reported that individuals with autism spectrum disorders (ASD) exhibited atypical patterns of facial muscle activity in response to facial expression stimuli. However, whether such activity is expressed in visible facial mimicry remains unknown. To investigate this issue, we videotaped facial responses in high-functioning individuals with ASD and controls to dynamic and static facial expressions of anger and happiness. Visual coding of facial muscle activity and the subjective impression ratings showed reduced congruent responses to dynamic expressions in the ASD group. Additionally, this decline was related to social dysfunction. These results suggest that impairment in overt facial mimicry in response to others' dynamic facial expressions may underlie difficulties in reciprocal social interaction among individuals with ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral impairment in social interactions. Although theoretical and empirical evidence suggests that impairment in the social brain network could be the neural underpinnings of ASD, previous structural magnetic resonance imaging (MRI) studies in adults with ASD have not provided clear support for this, possibly due to confounding factors, such as language impairments. To further explore this issue, we acquired structural MRI data and analyzed gray matter volume in adults with ASD (n = 36) who had no language impairments (diagnosed with Asperger’s disorder or pervasive developmental disorder not otherwise specified, with symptoms milder than those of Asperger’s disorder), had no comorbidity, and were not taking medications, and in age- and sex-matched typically developing (TD) controls (n = 36). Univariate voxel-based morphometry analyses revealed that regional gray matter volume was lower in the ASD than in the control group in several brain regions, including the right inferior occipital gyrus, left fusiform gyrus, right middle temporal gyrus, bilateral amygdala, right inferior frontal gyrus, right orbitofrontal cortex, and left dorsomedial prefrontal cortex. A multivariate approach using a partial least squares (PLS) method showed that these regions constituted a network that could be used to discriminate between the ASD and TD groups. A PLS discriminant analysis using information from these regions showed high accuracy, sensitivity, specificity, and precision (>80%) in discriminating between the groups. These results suggest that reduced gray matter volume in the social brain network represents the neural underpinnings of behavioral social malfunctioning in adults with ASD.