Gut CD4+ T cell phenotypes are a continuum molded by microbes, not by TH archetypes

CD4+ effector lymphocytes (Teff) are traditionally classified by the cytokines they produce. To determine the states that Teff cells actually adopt in frontline tissues in vivo, we applied single-cell transcriptome and chromatin analyses to colonic Teff cells in germ-free or conventional mice or in mice after challenge with a range of phenotypically biasing microbes. Unexpected subsets were marked by the expression of the interferon (IFN) signature or myeloid-specific transcripts, but transcriptome or chromatin structure could not resolve discrete clusters fitting classic helper T cell (TH) subsets. At baseline or at different times of infection, transcripts encoding cytokines or proteins commonly used as TH markers were distributed in a polarized continuum, which was functionally validated. Clones derived from single progenitors gave rise to both IFN-γ- and interleukin (IL)-17-producing cells. Most of the transcriptional variance was tied to the infecting agent, independent of the cytokines produced, and chromatin variance primarily reflected activities of activator protein (AP)-1 and IFN-regulatory factor (IRF) transcription factor (TF) families, not the canonical subset master regulators T-bet, GATA3 or RORγ

Colour Television : A Theory of Colour Reproduction

399 tr. ; 22 cm

Ecological assessment of wetland ecosystems of northern Kazakhstan on the basis of hydrochemistry and algal biodiversity

We studied diversity of algae and cyanobacteria in the wetlands of protected natural lakes with salinity ranging from 0.19 up to 32.7 in the arid/semiarid regions of Northern Kazakhstan. In plankton and periphyton of 34 lakes, we found 254 species belonging to 113 genera of 8 algal divisions. The diversity in arid regions is represented by widespread species of diatoms, green algae, and cyanobacteria in similar proportions. Alkaliphiles, among the indicators of acidification, and betamesosaprobionts, among the indicators of saprobity, predominated. The indices of saprobity in lakes varied from 1.47 to 2.7, reflecting low-trophic and low anthropogenically disturbed wetlands. Oligohalobes- -indifferents are most common. Highly diverse algal communities were found irrespective of various levels of mineralization. As a consequence of aridization, salinity increase suppressed algal diversity. The mineralization was the most important variable defining the diversity levels, irrespective of the type and location of wetland lakes in the arid regions

A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency

Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) and key regulator of immune cell development and function. We report a recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) in seven patients from six unrelated families. The patients exhibited profound susceptibility to opportunistic infections, notably Pneumocystis jirovecii, and presented with agammaglobulinemia. Patients' B cells showed impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation, whereas their T cells contained reduced TH(17) and T(FH) populations and exhibited decreased cytokine production. A knock-in mouse model of heterozygous T95R showed a severe defect in antibody production both at the steady state and after immunization with different types of antigens, consistent with the CID observed in these patients. The IRF4(T95R) variant maps to the TF's DNA binding domain, alters its canonical DNA binding specificities, and results in a simultaneous multimorphic combination of loss, gain, and new functions for IRF4. IRF4(T95R) behaved as a gain-of-function hypermorph by binding to DNA with higher affinity than IRF4(WT). Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, showcasing a hypomorphic activity of IRF4(T95R). Simultaneously, IRF4(T95R) functions as a neomorph by binding to noncanonical DNA sites to alter the gene expression profile, including the transcription of genes exclusively induced by IRF4(T95R) but not by IRF4(WT). This previously undescribed multimorphic IRF4 pathophysiology disrupts normal lymphocyte biology, causing human disease