The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Quantitative and qualitative deficits in neonatal lung-migratory dendritic cells impact the generation of the CD8+ T cell response.

CD103+ and CD11b+ populations of CD11c+MHCIIhi murine dendritic cells (DCs) have been shown to carry antigens from the lung through the afferent lymphatics to mediastinal lymph nodes (MLN). We compared the responses of these two DC populations in neonatal and adult mice following intranasal infection with respiratory syncytial virus. The response in neonates was dominated by functionally-limited CD103+ DCs, while CD11b+ DCs were diminished in both number and function compared to adults. Infecting mice at intervals through the first three weeks of life revealed an evolution in DC phenotype and function during early life. Using TCR transgenic T cells with two different specificities to measure the ability of CD103+ DC to induce epitope-specific CD8+ T cell responses, we found that neonatal CD103+ DCs stimulate proliferation in a pattern distinct from adult CD103+ DCs. Blocking CD28-mediated costimulatory signals during adult infection demonstrated that signals from this costimulatory pathway influence the hierarchy of the CD8+ T cell response to RSV, suggesting that limited costimulation provided by neonatal CD103+ DCs is one mechanism whereby neonates generate a distinct CD8+ T cell response from that of adults

Modulating CD28-mediated costimulatory signals differentially affects K^dM2_82–90 and D^bM_187–195-specific responses.

<p>A) Mice were infected with RSV on day 0 and subsequently given IP injections of 20 µg each of antibodies against CD80 and CD86 at the indicated day post-infection. Epitope-specific CD8+ T cell responses were measured by surface and tetramer staining at 7 days post-infection. All groups were compared using a two-way ANOVA and Tukey's multiple comparisons tests, and there were no significant differences in the D^bM_187–195 response. Differences between the K^dM2_82–90 response on Day 2 and other groups are indicated below the figure (* p≤0.05, *** p≤0.001, **** p≤0.0001). B) The response ratio/immunodominance profile of CD8+ T cell responses was obtained for each mouse by dividing the K^dM2_82–90 response by the response to D^bM_187–195. * indicates p≤0.05 following one-way ANOVA and Dunnett's multiple comparisons test. C) Day 7 CD8+ T cell responses of mice injected with the indicated dose of anti-CD80 and CD86 at day 2 post-infection or isotype control antibodies (either 50 µg or 20 µg). All groups were compared using a two-way ANOVA and Tukey's multiple comparisons tests. Differences in the K^dM2_82–90 response between the 50 and 25 µg groups and all other groups are indicated below the figure (ns not significant, ** p≤0.01, and **** p≤0.0001). The D^bM_187–195 responses are significantly different between both the 50 and the 25 µg groups and isotype (p≤0.01) only. D) CD8+ T cell response ratios of mice treated with each dose of anti-CD80 and CD86 antibodies. Groups were compared with a one-way ANOVA and Tukey's multiple comparisons test (** p≤0.01, *** p≤0.001, **** p≤0.0001), and all error bars represent the SEM.</p

RSV infection of lung migratory dendritic cell populations in the lung and draining mediastinal lymph node.

<p>Percent of infected (GFP+) dendritic cell populations in the lung (A and B) and the posterior mediastinal lymph node (MLN, C and D) at days 1–3 post-infection. Lung and MLN DC populations were gated as described in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003934#ppat.1003934.s001" target="_blank">Figure S1</a> and <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003934#ppat.1003934.s002" target="_blank">S2</a>, respectively. Percent GFP+ of CD103+ DCs (A and C) and CD11b+ DCs (B and D) was determined by comparison to mice infected at the same time with wtRSV. Data is representative of two experiments done with two pooled samples of 3–7 mice each and the error bars represent the SEM. * p≤0.05, **p≤0.01, ***p≤0.001, ns is no significance by two-way ANOVA and Sidak's multiple comparisons test.</p

Lung-migratory dendritic cell responses change dramatically during early life.

<p>CD103+ and CD11b+ DC populations in the MLN three days post-RSV infection were measured in mice of different ages. A) DC populations as a percent of CD11c+-gated cells of mice infected at the indicated age. B) Ratio of CD103+ to CD11b+ cells in the MHC Class II high gate. C) Total number of DC cells acquired on the flow cytometer per mouse after running samples to completion. Data in A and C are representative of three experiments using mice at available ages, and B represents data compiled from three independent experiments. Groups were compared using a two-way or one-way ANOVA and Tukey's multiple comparisons tests in GraphPad Prism and significant differences within the 7–21 day transition period are indicated (* p≤0.05, ** p≤0.01, ***p≤0.001, **** p≤0.0001). Error bars represent the SEM.</p

Age-dependent phenotypic changes in the CD103+ and CD11b+ DC populations in the MLN three days post-infection.

<p>A) Evaluation of the Class II high populations of neonatal (7 days old) vs. adult mice shows differences in composition and phenotype of DC populations. B) Costimulatory molecule (CD86, CD80 and CD70) expression was measured by flow cytometry on CD103+ and CD11b+ DCs three days post-infection at the indicated age and the mean fluorescence intensity (MFI) is displayed. Data are representative of three experiments using two to three samples of lymph nodes pooled from 3–7 mice. Error bars indicate the SEM, and all data was analyzed using one-way ANOVA with Tukey's multiple comparisons test (* p≤0.05, ** p≤0.01, *** p≤0.001, **** p≤0.0001).</p

Cytokine production following 5 hour stimulation of TCR Tg cells.

<p>Cells were stimulated in the presence of specific peptide in graded concentrations for 5+CD8+ cells expressing each cytokine was determined by intracellular cytokine staining. Data are representative of two independent experiments, 1–2 mice in each.</p

Tetramer dilution assay.

<p>(A) Splenocytes from TCR Tg mice were processed and stained with serially (1∶2) diluted PE-conjugated K^dM2_82–90 tetramer. Data are presented as the percentage of original MFI in CD3+ CD8+ cells stained with non-diluted tetramer. Data are representative of 3 independent experiments 1–2 mice in each. (B) Vβ expression was measured on CD8+ T cells from the blood of TRBV13-1 and TRBV13-2 TCR Tg strains.</p

Description of TCR Tg strains.

<p>Description of TCR Tg strains.</p