The guanine nucleotide exchange factor Rin-like controls Tfh cell differentiation via CD28 signaling.

T follicular helper (Tfh) cells are essential for the development of germinal center B cells and high-affinity antibody-producing B cells in humans and mice. Here, we identify the guanine nucleotide exchange factor (GEF) Rin-like (Rinl) as a negative regulator of Tfh generation. Loss of Rinl leads to an increase of Tfh in aging, upon in vivo immunization and acute LCMV Armstrong infection in mice, and in human CD4+ T cell in vitro cultures.

The Tyrosine Kinase Tec Regulates Effector Th17 Differentiation, Pathogenicity, and Plasticity in T-Cell-Driven Intestinal Inflammation.

T helper (Th) 17 cells are not only key in controlling infections mediated by extracellular bacteria and fungi but are also triggering autoimmune responses. Th17 cells comprise heterogeneous subsets, some with pathogenic functions. They can cease to secrete their hallmark cytokine IL-17A and even convert to other T helper lineages, a process known as transdifferentiation relying on plasticity.

24-Norursodeoxycholic acid reshapes immunometabolism in CD8 T cells and alleviates hepatic inflammation.

Background & Aims: 24-Norursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid used to treat immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC), where dysregulated T cells including CD8 T cells contribute to hepatobiliary immunopathology. We hypothesized that NorUDCA may directly modulate CD8 T cell function thus contributing to its therapeutic efficacy.

Methods: NorUDCA's immunomodulatory effects were first studied in Mdr2 mice, as a cholestatic model of PSC.

Complex Interplay Between MAZR and Runx3 Regulates the Generation of Cytotoxic T Lymphocyte and Memory T Cells.

The BTB zinc finger transcription factor MAZR (also known as PATZ1) controls, partially in synergy with the transcription factor Runx3, the development of CD8 lineage T cells. Here we explored the role of MAZR as well as combined activities of MAZR/Runx3 during cytotoxic T lymphocyte (CTL) and memory CD8 T cell differentiation. In contrast to the essential role of Runx3 for CTL effector function, the deletion of MAZR had a mild effect on the generation of CTLs .

Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation.

Some effector CD4+ T cell subsets display cytotoxic activity, thus breaking the functional dichotomy of CD4+ helper and CD8+ cytotoxic T lymphocytes. However, molecular mechanisms regulating CD4+ cytotoxic T lymphocyte (CD4+ CTL) differentiation are poorly understood. Here we show that levels of histone deacetylases 1 and 2 (HDAC1-HDAC2) are key determinants of CD4+ CTL differentiation.

The Transcription Factor MAZR/PATZ1 Regulates the Development of FOXP3 Regulatory T Cells.

Forkhead box protein P3 (FOXP3) regulatory T cells (T cells) play a key role in maintaining tolerance and immune homeostasis. Here, we report that a T cell-specific deletion of the transcription factor MAZR (also known as PATZ1) leads to an increased frequency of T cells, while enforced MAZR expression impairs T cell differentiation. Further, MAZR expression levels are progressively downregulated during thymic T cell development and during in-vitro-induced human T cell differentiation, suggesting that MAZR protein levels are critical for controlling T cell development.

Oncostatin-M-Reactive Pericytes Aggravate Blood-Brain Barrier Dysfunction by Activating JAK/STAT3 Signaling In Vitro.

Oncostatin M (OSM) is a cytokine of the interleukin (IL)-6 family members. It induces blood-brain barrier (BBB) dysfunction by activating Janus-activated kinase (JAK) and signal transducer and activator of transcription (STAT) 3 pathways in brain endothelial cells. Brain pericytes located around microvessels are one of the BBB constituents.

The zinc-finger transcription factor MAZR regulates iNKT cell subset differentiation.

Invariant natural killer T (iNKT) cells represent a subgroup of innate-like T cells and play an important role in immune responses against certain pathogens. In addition, they have been linked to autoimmunity and antitumor immunity. iNKT cells consist of several subsets with distinct functions; however, the transcriptional networks controlling iNKT subset differentiation are still not fully characterized.

Differential Requirement of Enhancers E8 and E8 in Cytotoxic Lineage T Cells and in Intestinal Intraepithelial Lymphocytes.

CD8 expression in T lymphocytes is tightly regulated by the activity of at least six enhancers (E8-E8), however their complex developmental stage-, subset-, and lineage-specific interplays are incompletely understood. Here we analyzed ATAC-seq data on the Immunological Genome Project database and identified a similar developmental regulation of chromatin accessibility of a subregion of E8, designated E8-core, and of E8. Loss of E8-core led to a similar reduction in CD8 expression in naïve CD8 T cells and in IELs as observed in mice, demonstrating that we identified the core enhancer region of E8.

Oncostatin M-induced blood-brain barrier impairment is due to prolonged activation of STAT3 signaling in vitro.

Oncostatin M (OSM) is a member of the interleukin (IL)-6 family cytokines. We previously demonstrated that OSM induces blood-brain barrier (BBB) impairment. However, functional characterization of IL-6 family cytokines in BBB regulation and the cytokine-related intracellular signaling pathway remain unclear.

The corepressor NCOR1 regulates the survival of single-positive thymocytes.

Nuclear receptor corepressor 1 (NCOR1) is a transcriptional regulator bridging repressive chromatin modifying enzymes with transcription factors. NCOR1 regulates many biological processes, however its role in T cells is not known. Here we show that Cd4-Cre-mediated deletion of NCOR1 (NCOR1 cKO) resulted in a reduction of peripheral T cell numbers due to a decrease in single-positive (SP) thymocytes.

Acetylation of the Cd8 Locus by KAT6A Determines Memory T Cell Diversity.

How functionally diverse populations of pathogen-specific killer T cells are generated during an immune response remains unclear. Here, we propose that fine-tuning of CD8αβ co-receptor levels via histone acetylation plays a role in lineage fate. We show that lysine acetyltransferase 6A (KAT6A) is responsible for maintaining permissive Cd8 gene transcription and enabling robust effector responses during infection.

DNA Repair Cofactors ATMIN and NBS1 Are Required to Suppress T Cell Activation.

Proper development of the immune system is an intricate process dependent on many factors, including an intact DNA damage response. The DNA double-strand break signaling kinase ATM and its cofactor NBS1 are required during T cell development and for the maintenance of genomic stability. The role of a second ATM cofactor, ATMIN (also known as ASCIZ) in T cells is much less clear, and whether ATMIN and NBS1 function in synergy in T cells is unknown.

MAZR and Runx Factors Synergistically Repress ThPOK during CD8+ T Cell Lineage Development.

Th-inducing Pox virus and zinc finger/Krüppel-like factor (ThPOK) is a key commitment factor for CD4(+) lineage T cells and is essential for the maintenance of CD4 lineage integrity; thus, the expression of ThPOK has to be tightly controlled. In this article, we demonstrate that Myc-associated zinc finger-related factor (MAZR) and Runt-related transcription factor 1 (Runx1) together repressed ThPOK in preselection double-positive thymocytes, whereas MAZR acted in synergy with Runx3 in the repression of ThPOK in CD8(+) T cells. Furthermore, MAZR-Runx1 and MAZR-Runx3 double-mutant mice showed enhanced derepression of Cd4 in double-negative thymocytes and in CD8(+) T cells in comparison with Runx1 or Runx3 single-deficient mice, respectively, indicating that MAZR modulates Cd4 silencing.

PATZ1 Is a DNA Damage-Responsive Transcription Factor That Inhibits p53 Function.

Insults to cellular health cause p53 protein accumulation, and loss of p53 function leads to tumorigenesis. Thus, p53 has to be tightly controlled. Here we report that the BTB/POZ domain transcription factor PATZ1 (MAZR), previously known for its transcriptional suppressor functions in T lymphocytes, is a crucial regulator of p53.

A novel Cd8-cis-regulatory element preferentially directs expression in CD44hiCD62L+ CD8+ T cells and in CD8αα+ dendritic cells.

CD8 coreceptor expression is dynamically regulated during thymocyte development and is tightly controlled by the activity of at least 5 different cis-regulatory elements. Despite the detailed characterization of the Cd8 loci, the regulation of the complex expression pattern of CD8 cannot be fully explained by the activity of the known Cd8 enhancers. In this study, we revisited the Cd8ab gene complex with bioinformatics and transgenic reporter gene expression approaches to search for additional Cd8 cis-regulatory elements.

CD4(+) T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2.

Molecular mechanisms that maintain lineage integrity of helper T cells are largely unknown. Here we show histone deacetylases 1 and 2 (HDAC1 and HDAC2) as crucial regulators of this process. Loss of HDAC1 and HDAC2 during late T cell development led to the appearance of major histocompatibility complex (MHC) class II-selected CD4(+) helper T cells that expressed CD8-lineage genes such as Cd8a and Cd8b1.

The transcription factor MAZR preferentially acts as a transcriptional repressor in mast cells and plays a minor role in the regulation of effector functions in response to FcεRI stimulation.

Mast cells are key players in type I hypersensitivity reactions in humans and mice and their activity has to be tightly controlled. Previous studies implicated the transcription factor MAZR in the regulation of mast cell function. To study the role of MAZR in mast cells, we generated a conditional Mazr allele and crossed Mazr (F/F) mice with the Vav-iCre deleter strain, which is active in all hematopoietic cells.

Metformin induces up-regulation of blood-brain barrier functions by activating AMP-activated protein kinase in rat brain microvascular endothelial cells.

Blood-brain barrier (BBB) disruption occurs frequently in CNS diseases and injuries. Few drugs have been developed as therapeutic candidates for facilitating BBB functions. Here, we examined whether metformin up-regulates BBB functions using rat brain microvascular endothelial cells (RBECs).

Transcriptional reprogramming of mature CD4⁺ helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes.

TCRαβ thymocytes differentiate into either CD8αβ(+) cytotoxic T lymphocytes or CD4(+) helper T cells. This functional dichotomy is controlled by key transcription factors, including the helper T cell master regulator ThPOK, which suppresses the cytolytic program in major histocompatibility complex (MHC) class II-restricted CD4(+) thymocytes. ThPOK continues to repress genes of the CD8 lineage in mature CD4(+) T cells, even as they differentiate into effector helper T cell subsets.

Cd8 enhancer E8I and Runx factors regulate CD8α expression in activated CD8+ T cells.

Cd8a and Cd8b1 coreceptor gene (Cd8) expression is tightly controlled during T-cell development by the activity of five Cd8 enhancers (E8(I)-E8(V)). Here we demonstrate a unique transcriptional program regulating CD8 expression during CD8(+) effector T-cell differentiation. The Cd8 enhancer E8(I) and Runx/core-binding factor-β (CBFβ) complexes were required for the establishment of this regulatory circuit, because E8(I)-, Runx3-, or CBFβ-deficient CD8(+) T cells down-regulated CD8α expression during activation.

The zinc-finger protein MAZR is part of the transcription factor network that controls the CD4 versus CD8 lineage fate of double-positive thymocytes.

The CD4 versus CD8 lineage specification of thymocytes is linked to coreceptor expression. The transcription factor MAZR has been identified as an important regulator of Cd8 expression. Here we show that variegated CD8 expression by loss of Cd8 enhancers was reverted in MAZR-deficient mice, which confirms that MAZR negatively regulates the Cd8 loci during the transition to the double-positive (DP) stage.

A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity.

A conundrum of innate antiviral immunity is how nucleic acid-sensing Toll-like receptors (TLRs) and RIG-I/MDA5 receptors cooperate during virus infection. The conventional wisdom has been that the activation of these receptor pathways evokes type I IFN (IFN) responses. Here, we provide evidence for a critical role of a Toll-like receptor 3 (TLR3)-dependent type II IFN signaling pathway in antiviral innate immune response against Coxsackievirus group B serotype 3 (CVB3), a member of the positive-stranded RNA virus family picornaviridae and most prevalent virus associated with chronic dilated cardiomyopathy.

Impaired T-cell development in the absence of Vav1 and Itk.

Vav1 and the Tec family kinase Itk act in similar T-cell activation pathways. Both molecules interact with members of the Cbl family of E3 ubiquitin ligases, and signaling defects in Vav1(-/-) T cells are rescued upon deletion of Cbl-b. In this study we investigate the relation between Itk and Cbl-b or Vav1 by generating Itk/Cbl-b and Itk/Vav1 double-deficient mice.