MHC class II antigen presentation by intestinal epithelial cells fine-tunes bacteria-reactive CD4 T cell responses.

Although intestinal epithelial cells (IECs) can express major histocompatibility complex class II (MHC II), especially during intestinal inflammation, it remains unclear if antigen presentation by IECs favours pro- or anti-inflammatory CD4+ T cell responses. Using selective gene ablation of MHC II in IECs and IEC organoid cultures, we assessed the impact of MHC II expression by IECs on CD4+ T cell responses and disease outcomes in response to enteric bacterial pathogens. We found that intestinal bacterial infections elicit inflammatory cues that greatly increase expression of MHC II processing and presentation molecules in colonic IECs. Whilst IEC MHC II expression had little impact on disease severity following Citrobacter rodentium or Helicobacter hepaticus infection, using a colonic IEC organoid-CD4+ T cell co-culture system, we demonstrate that IECs can activate antigen-specific CD4+ T cells in an MHC II-dependent manner, modulating both regulatory and effector Th cell subsets. Furthermore, we assessed adoptively transferred H. hepaticus-specific CD4+ T cells during intestinal inflammation in vivo and report that IEC MHC II expression dampens pro-inflammatory effector Th cells. Our findings indicate that IECs can function as non-conventional antigen presenting cells and that IEC MHC II expression fine-tunes local effector CD4+ T cell responses during intestinal inflammation.

Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3⁺ Treg cell function in the intestine.

Elevated levels of interleukin-18 (IL-18) are found in many chronic inflammatory disorders, including inflammatory bowel disease (IBD), and polymorphisms in the IL18R1-IL18RAP locus are associated with IBD susceptibility. IL-18 is an IL-1 family cytokine that has been proposed to promote barrier function in the intestine, but the effects of IL-18 on intestinal CD4(+) T cells are poorly understood. Here we demonstrate that IL-18R1 expression is enhanced on both effector and regulatory CD4(+) T cells in the intestinal lamina propria, with T helper type 17 (Th17) cells exhibiting particularly high levels. We further show that, during steady state, intestinal epithelial cells constitutively secrete IL-18 that acts directly on IL-18R1-expressing CD4(+) T cells to limit colonic Th17 cell differentiation, in part by antagonizing IL-1R1 signaling. In addition, although IL-18R1 is not required for colonic Foxp3(+) regulatory T (Treg) cell differentiation, we found that IL-18R1 signaling was critical for Foxp3(+) Treg cell-mediated control of intestinal inflammation, where it promoted the expression of key Treg effector molecules. Thus IL-18 is a key epithelial-derived cytokine that differentially regulates distinct subsets of intestinal CD4(+) T cells during both homeostatic and inflammatory conditions, a finding with potential implications for treatment of chronic inflammatory disorders.

A genetic study of ADHD and activity level in infancy.

It is well known that there are strong genetic influences on attention-deficit hyperactivity disorder (ADHD), with genetic association studies providing good evidence for the involvement of the dopamine neurotransmitter system in its aetiology. Developmental origins of ADHD represent an interesting area of research to understand the genetics that underlie early appearing individual differences. However, understanding the molecular basis of ADHD requires accurate, unbiased, heritable measures that can be used for molecular genetic association analyses. We take two approaches to examine the genetics of ADHD behaviours in infancy. Using quantitative genetic techniques, we explore the relationship between objective measures of activity level (AL) in both home and laboratory environments as well as with parent ratings of ADHD symptoms in a population sample of 2-year-old twins. Molecular association analyses of these measures examine candidate genes previously associated with ADHD. We find that ADHD symptoms, AL in the home and AL in the lab represent heritable phenotypes in 2-year-old infants. AL measured in the home has a strong genetic correlation with symptoms of ADHD, whereas AL in the lab correlates only modestly with the same ADHD measure. Genetic correlations suggest that AL in the home is more comparable than AL in the lab to ADHD behaviour and support the separation of all three for molecular analyses. There was modest evidence for association between DAT1, NET1 and ADHD symptom scores, as well as between DAT1 and AL in the lab.