Epidermal loss of Bcl6 exacerbates MC903-induced atopic dermatitis-like skin inflammation.

Atopic dermatitis (AD) is a chronic inflammatory skin disease where Th2-type immune responses are dominant. In the lesional skin of AD, keratinocytes show differentiation defects and secrete proinflammatory cytokines and chemokines, amplifying Th2-type responses in AD. We previously reported that inducible loss of B-cell lymphoma 6 (Bcl6), a transcription repressor and a master transcriptional regulator of follicular helper T cells and germinal center B cells, in the whole body results in upregulation of Th2-related cytokines in mouse skin.

Bcl6 is a subset-defining transcription factor of lymphoid tissue inducer-like ILC3.

Innate lymphoid cells (ILCs) are tissue-resident effector cells with roles in tissue homeostasis, protective immunity, and inflammatory disease. Group 3 ILCs (ILC3s) are classically defined by the master transcription factor RORγt. However, ILC3 can be further subdivided into subsets that share type 3 effector modules that exhibit significant ontological, transcriptional, phenotypic, and functional heterogeneity.

High Expression Indicates Poor Prognosis in Prostate Cancer.

Background/aim: High expression of solute carrier family 20 member 1 (SLC20A1) indicates poor clinical outcomes for patients with breast cancer subtypes treated with endocrine therapy and radiotherapy. However, the association between SLC20A1 expression and clinical outcomes in prostate cancer remains to be determined.

Materials And Methods: Open-source datasets (The Cancer Genome Atlas prostate, Stand Up to Cancer-Prostate Cancer Foundation Dream Team, and The Cancer Genome Atlas PanCancer Atlas) were downloaded and analyzed.

Spatiotemporal resolution of germinal center Tfh cell differentiation and divergence from central memory CD4 T cell fate.

Follicular helper T (Tfh) cells are essential for germinal center (GC) B cell responses. However, it is not clear which PD-1CXCR5Bcl6CD4 T cells will differentiate into PD-1CXCR5Bcl6 GC-Tfh cells and how GC-Tfh cell differentiation is regulated. Here, we report that the sustained Tigit expression in PD-1CXCR5CD4 T cells marks the precursor Tfh (pre-Tfh) to GC-Tfh transition, whereas TigitPD-1CXCR5CD4 T cells upregulate IL-7Rα to become CXCR5CD4 T memory cells with or without CCR7.

Foxp3 and Bcl6 deficiency synergistically induces spontaneous development of atopic dermatitis-like skin disease.

Atopic dermatitis (AD) is a common chronic skin disease caused by immune dysfunction, specifically the hyperactivation of Th2 immunity. AD is a complex disease with multiple factors contributing to its development; however, the interaction between these factors is not fully understood. In this study, we demonstrated that the conditional deletion of both the forkhead box p3 (Foxp3) and B-cell lymphoma 6 (Bcl6) genes induced the spontaneous development of AD-like skin inflammation with hyperactivation of type 2 immunity, skin barrier dysfunction, and pruritus, which were not induced by the single deletion of each gene.

High expression of PKCλ and ALDH1A3 indicates a poor prognosis, and PKCλ is required for the asymmetric cell division of ALDH1A3-positive cancer stem cells in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is the cancer with the poorest prognosis. One of the major properties reflecting its poor prognosis is high-grade heterogeneity, which leads to insensitivity to anticancer treatments. Cancer stem cells (CSCs) acquire phenotypic heterogeneity, generating abnormally differentiated cells by asymmetric cell division.

Dysfunction of Foxp3 Regulatory T Cells Induces Dysbiosis of Gut Microbiota via Aberrant Binding of Immunoglobulins to Microbes in the Intestinal Lumen.

Foxp3 regulatory T (Treg) cells prevent excessive immune responses against dietary antigens and commensal bacteria in the intestine. Moreover, Treg cells contribute to the establishment of a symbiotic relationship between the host and gut microbes, partly through immunoglobulin A. However, the mechanism by which Treg cell dysfunction disturbs the balanced intestinal microbiota remains unclear.

High Expression of and Predicts a Poor Prognosis in Basal-like Breast Cancer.

Background/aim: CD58 is an immune adhesion molecule on the cellular surface. It was previously found that a high expression of CD58 predicted a poor prognosis of patients with lower-grade gliomas. Therefore, the aim of this paper was to investigate the association between CD58 and breast cancer.

High Expression of and Is Associated With Poor Prognosis in Luminal B Breast Cancer.

Background/aim: p62 (also known as sequestosome 1) is involved in cancer progression, and high expression of p62 indicates poor clinical outcome in several cancer types. However, the association between p62 gene expression and cancer stem cells (CSCs) in breast cancer subtypes remains unclear.

Materials And Methods: In the present study, genomic datasets of primary breast cancer (The Cancer Genome Atlas, n=593; and Molecular Taxonomy of Breast Cancer International Consortium, n=2,509) were downloaded.

Gasdermin D-mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma.

Long-term senescent cells exhibit a secretome termed the senescence-associated secretory phenotype (SASP). Although the mechanisms of SASP factor induction have been intensively studied, the release mechanism and how SASP factors influence tumorigenesis in the biological context remain unclear. In this study, using a mouse model of obesity-induced hepatocellular carcinoma (HCC), we identified the release mechanism of SASP factors, which include interleukin-1β (IL-1β)- and IL-1β-dependent IL-33, from senescent hepatic stellate cells (HSCs) via gasdermin D (GSDMD) amino-terminal-mediated pore.

GLO 1 and PKCλ Regulate ALDH1-positive Breast Cancer Stem Cell Survival.

Background/aim: We examined the inhibitory effects of both glyoxalase 1 (GLO 1) and protein kinase C (PKC)λ in aldehyde dehydrogenase 1 (ALDH1)-positive breast cancer stem cells (CSCs).

Materials And Methods: Breast cancer genomics datasets (TCGA, n=593; METABRIC, n=1904) were downloaded and statistically analyzed. The effects of GLO 1 and PKCλ on trypan blue staining and tumor-sphere formation by ALDH1 cells derived from triple negative breast cancer (TNBC) and basal-like breast cancer were examined.

High Expression Is Associated With Poor Prognoses in Claudin-low and Basal-like Breast Cancers.

Background/aim: SLC20A1 has been identified as a prognostic marker in ER+ breast cancer. However, the role of SLC20A1 expression in breast cancer subtypes other than the ER+ types remains unclear.

Materials And Methods: Genomics datasets were downloaded and analyzed, and the effect of SLC20A1 knockdown using targeted siRNA on cell viability and tumor-sphere formation was assessed.

Microbiota-derived butyrate limits the autoimmune response by promoting the differentiation of follicular regulatory T cells.

Background: Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder with a high prevalence, especially in industrialized countries. Dysbiosis of the intestinal microbiota has been observed in RA patients. For instance, new-onset untreated RA (NORA) is associated with the underrepresentation of the Clostridium cluster XIVa, including Lachnospiraceae, which are major butyrate producers, although the pathological relevance has remained obscure.

High PKCλ expression is required for ALDH1-positive cancer stem cell function and indicates a poor clinical outcome in late-stage breast cancer patients.

Despite development of markers for identification of cancer stem cells, the mechanism underlying the survival and division of cancer stem cells in breast cancer remains unclear. Here we report that PKCλ expression was enriched in basal-like breast cancer, among breast cancer subtypes, and was correlated with ALDH1A3 expression (p = 0.016, χ2-test).

Spontaneous antibody production caused by regulatory T cell deficiency occurs through a germinal center-independent pathway.

Foxp3 regulatory T cells (Tregs) are essential for the prevention of autoantibody and allergen-specific IgE production. Treg deficiency causes an elevation of the serum levels of these pathogenic antibodies, accompanied by spontaneous germinal center (GC) formation. However, it remains to be determined whether excessive and pathogenic antibody production induced by Treg deficiency requires a GC response.

High Expression of , and Predicts a Poor Prognosis in Late-stage Breast Cancer.

Background/aim: Co-expression of c-Met and ALDH1A3 indicates a poor prognosis in stage III-IV breast cancers and contributes to cell proliferation and tumor formation by ALDH1-positive breast CSCs. PKCλ is overexpressed and contributes to a poor prognosis in several cancers.

Materials And Methods: A breast cancer genomics data set (METABRIC, n=2509) was downloaded and analyzed, as was the effect c-Met and PKCλ inhibitors on ALDH1 cell viability and tumor-sphere formation.

Dysregulation of humoral immunity in Foxp3 conditional-knockout mice.

Foxp3 regulatory T cells (Tregs) are crucial for maintaining tolerance to self-antigens and preventing autoimmune diseases. Loss of Foxp3 expression leads to autoimmunity and disrupts humoral immune responses, including hyperproduction of immunoglobulin E (IgE). Elucidation of how Tregs control antibody production can lead to the development of new therapies for autoimmune and allergic diseases.

A novel mouse model for tracking the fate of CXCR5-expressing T cells.

The germinal center (GC) reaction, a critical process in the humoral immune response, requires follicular helper T (Tfh) cells. Tfh cells express the master transcription factor Bcl6 and chemokine receptor CXCR5, which enable them to migrate from the T cell zone to B cell follicles and interact with GC B cells. However, CXCR5 is downregulated when Tfh cells become memory cells.

Quantitative analysis by surface plasmon resonance of CD28 interaction with cytoplasmic adaptor molecules Grb2, Gads and p85 PI3K.

CD28 surface receptors provide co-stimulatory signals that are required for full T cell activation. The CD28 cytoplasmic region has one YMNM and two PXXP motifs as a functional motif. Upon CD28 ligation, Grb2, Gads, and the p85 subunit of PI3 kinase are recruited to the CD28 cytoplasmic region.

The 3' enhancer CNS2 is a critical regulator of interleukin-4-mediated humoral immunity in follicular helper T cells.

A main role for interleukin-4 (IL-4) is in humoral immunity, and follicular helper CD4(+) T (Tfh) cells may be an intrinsic IL-4 source. Here we demonstrate that conserved noncoding sequence 2 (CNS2) is an essential enhancer element for IL-4 expression in Tfh cells but not in Th2 cells. Mice with a CNS2 deletion had a reduction in IgG1 and IgE production and in IL-4 expression in Tfh cells.

Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells.

The transcription factor Foxp3 is essential for optimal regulatory T (T reg) cell development and function. Here, we show that CD4(+) T cells from Cbl-b RING finger mutant knockin or Cbl-b-deficient mice show impaired TGF-beta-induced Foxp3 expression. These T cells display augmented Foxo3a phosphorylation, but normal TGF-beta signaling.

Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1.

Repeated injection of alpha-galactosylceramide, an agonistic ligand for natural killer T (NKT) cells, results in long-term unresponsiveness or anergy, which severely limits its clinical application. However, the molecular mechanisms leading to NKT anergy induction remain unclear. We show here that the decreased IFN-gamma production and failed tumor rejection observed in anergized NKT cells are rescued by Cbl-b deficiency.

Palmitoylation-dependent plasma membrane transport but lipid raft-independent signaling by linker for activation of T cells.

Linker for activation of T cells (LAT) is a dually palmitoylated transmembrane adaptor protein essential for T cell development and activation. However, whether LAT palmitoylation and/or lipid raft localization are required for its function is controversial. To address this question, we used a combination of biochemical, imaging, and genetic approaches, including LAT retrovirus-transduced mouse T cells and bone marrow chimeric mice.

CD28 stimulation triggers NF-kappaB activation through the CARMA1-PKCtheta-Grb2/Gads axis.

CD28 stimulation contributes to activation of the IL-2 promoter by up-regulating the activity of several transcription factors, including nuclear factor kappaB (NF-kappaB)/Rel family members. However, the signal-transducing cascades linking the CD28 molecule and activation of NF-kappaB remain unclear. Protein kinase C (PKC) , CARMA1 and Bcl10 have recently been reported to integrate TCR-mediated NF-kappaB activation.

Grb2 and Gads exhibit different interactions with CD28 and play distinct roles in CD28-mediated costimulation.

Although both CD28 and ICOS bind PI3K and provide stimulatory signal for T cell activation, unlike CD28, ICOS does not costimulate IL-2 secretion. CD28 binds both PI3K and Grb2, whereas ICOS binds only PI3K. We have generated an ICOS mutant, which can bind Grb2 by replacement of its PI3K binding motif YMFM with the CD28 YMNM motif, and shown that it induces significant activation of the IL-2 promoter.