To extend our understanding of the genetic basis of human immune function and dysfunction, we performed an expression quantitative trait locus (eQTL) study of purified CD4+ T cells and monocytes, representing adaptive and innate immunity, in a multi-ethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. We note an over-representation of T cell–specific eQTLs among susceptibility alleles for autoimmune diseases and of monocyte-specific eQTLs among Alzheimer’s and Parkinson’s disease variants. This polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants.

A T cell receptor transgenic mouse line reactive to a microbiota flagellin, CBir1, was used to define mechanisms of host microbiota homeostasis. Intestinal IgA, but not serum IgA, was found to block mucosal flagellin uptake and systemic T cell activation in mice. Depletion of CD4 ؉ CD25 ؉ Tregs decreased IgA ؉ B cells, total IgA, and CBir1-specific IgA in gut within days. Repletion of T celldeficient mice with either CD4 ؉ CD25 ؉ or CD4 ؉ foxp3 ؉ Tregs restored intestinal IgA to a much greater extent than their reciprocal CD4 ؉ subsets, indicating that Tregs are the major helper cells for IgA responses to microbiota antigens such as flagellin. We propose that the major role of this coordinated Treg-IgA response is to maintain commensalism with the microbiota.

SUMMARY Type-1 interferon (IFN) is a key mediator of organismal responses to pathogens, eliciting prototypical “Interferon Signature Genes” which encode antiviral and inflammatory mediators. For a global view of IFN signatures and regulatory pathways, we performed gene expression and chromatin analyses of the IFN-induced response across a range of immunocyte lineages. These distinguished ISGs by cell-type specificity, kinetics, and sensitivity to tonic IFN, and revealed underlying changes in chromatin configuration. We combined 1398 human and mouse datasets to computationally infer ISG modules and their regulators, validated by genetic analysis in both species. Some ISGs are controlled by Stat1/2 and Irf9 and the ISRE DNA motif, but others appeared dependent on non-canonical factors. This regulatory framework helped to interpret JAK1 blockade pharmacology, different clusters being affected under tonic or IFN-stimulated conditions, and the IFN signatures previously associated with human diseases, revealing unrecognized subtleties in disease footprints, as affected by human ancestry.

Much of the knowledge about cell differentiation and function in the immune system has come from studies in mice, but the relevance to human immunology, diseases, and therapy has been challenged, perhaps more from anecdotal than comprehensive evidence. To this end, we compare two large compendia of transcriptional profiles of human and mouse immune cell types. Global transcription profiles are conserved between corresponding cell lineages. The expression patterns of most orthologous genes are conserved, particularly for lineage-specific genes. However, several hundred genes show clearly divergent expression across the examined cell lineages, and among them, 169 genes did so even with highly stringent criteria. Finally, regulatory mechanisms—reflected by regulators’ differential expression or enriched cis -elements—are conserved between the species but to a lower degree, suggesting that distinct regulation may underlie some of the conserved transcriptional responses.

T lymphocyte activation by antigen conditions adaptive immune responses and immunopathologies, but we know little about its variation in humans, and its genetic or environmental roots. We analyzed gene expression in CD4+ T cells during unbiased activation or in Th17 conditions from 348 healthy subjects representing European, Asian and African ancestries. We observed inter-individual variability, most marked for cytokine transcripts, with clear biases on the basis of ancestry, and following patterns more complex than simple Th1/2/17 partitions. We identified 39 genetic loci specifically associated in cis with activated gene expression. We further fine-mapped and validated a single-base variant that modulates YY1 binding and the activity of an enhancer element controlling the autoimmune-associated IL2RA gene, affecting its activity in activated but not regulatory T cells. Thus, inter-individual variability affects the fundamental immunologic process of T helper activation, with important connections to autoimmune disease.

Little is known about how the microbiota regulates T cell proliferation and whether spontaneous T cell proliferation is involved in the pathogenesis of inflammatory bowel disease. In this study, we show that stimulation of innate pathways by microbiota-derived ligands and antigen-specific T cell stimulation are both required for intestinal inflammation. Microbiota-derived ligands promoted spontaneous T cell proliferation by activating dendritic cells (DCs) to produce IL-6 via Myd88, as shown by the spontaneous proliferation of T cells adoptively transferred into specific pathogen–free (SPF) RAG−/− mice, but not in germfree RAG−/− mice. Reconstitution of germfree RAG−/− mice with cecal bacterial lysate–pulsed DCs, but not with IL-6−/− or Myd88−/− DCs, restored spontaneous T cell proliferation. CBir1 TCR transgenic (CBir1 Tg) T cells, which are specific for an immunodominant microbiota antigen, induced colitis in SPF RAG−/− mice. Blocking the spontaneous proliferation of CBir1 Tg T cells by co-transferring bulk OT II CD4+ T cells abrogated colitis development. Although transferred OT II T cells underwent spontaneous proliferation in RAG−/− mice, the recipients failed to develop colitis because of the lack of cognate antigen in the intestinal lumen. Collectively, our data demonstrate that induction of colitis requires both spontaneous proliferation of T cells driven by microbiota-derived innate signals and antigen-specific T cell proliferation.

Theta sequences are circuit-level activity patterns produced when groups of hippocampal place cells fire in sequences that reflect a compressed behavioral order of place fields within each theta cycle. The high temporal coordination between place cells exhibited in theta sequences is compatible with the induction of synaptic plasticity and has been proposed as one of the mechanisms underlying the encoding of episodic memory of recently acquired experience. Yet how theta sequences develop with experience has not been directly addressed. Here we simultaneously recorded large numbers of cells in the dorsal hippocampal CA1 area from rats exploring on a novel linear track. Although place cell firing activities accurately represented the animal's current location, distinct theta sequences were absent on the first lap but emerged immediately thereafter and remained stable once established. The absence of theta sequences on the first lap was not due to place field instability, decreased overall excitability of place cells, behavior variables, or the absence of individual neuronal phase precession. We observed strong single-lap phase precession in a significant percentage of place fields on the first lap and throughout the recording. Individual neuronal phase precession was stable from the first lap to subsequent laps but, across neurons, phase precession became more synchronized after experience, suggesting a novel mechanism for the generation of theta sequences. These results suggest that experience-independent temporal coding in individual neurons is combined with rapid plasticity of hippocampal neural networks during experience to acquire predictive representations of the immediate future.

Curcumin (CUR) is a yellow polyphenolic compound derived from the plant turmeric. It is widely used to treat many types of diseases, including cancers such as those of lung, cervices, prostate, breast, bone and liver. However, its effectiveness has been limited due to poor aqueous solubility, low bioavailability and rapid metabolism and systemic elimination. To solve these problems, researchers have tried to explore novel drug delivery systems such as liposomes, solid dispersion, microemulsion, micelles, nanogels and dendrimers. Among these, liposomes have been the most extensively studied. Liposomal CUR formulation has greater growth inhibitory and pro-apoptotic effects on cancer cells. This review mainly focuses on the preparation of liposomes containing CUR and its use in cancer therapy.