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TCRαβ+CD8αα+ intraepithelial lymphocytes (CD8αα+ αβ IELs) are a specialized subset of T cells in the gut epithelium that develop from thymic agonist selected IEL precursors (IELps). The molecular mechanisms underlying the selection and differentiation of this T cell type in the thymus are largely unknown. Here, we found that Bcl6 deficiency in αβ T cells resulted in the near absence of CD8αα+ αβ IELs. BCL6 was expressed by approximately 50% of CD8αα+ αβ IELs and by the majority of thymic PD1+ IELps after agonist selection. Bcl6 deficiency blocked early IELp generation in the thymus, and its expression in IELps was induced by thymic TCR signaling in an ERK-dependent manner. As a result of Bcl6 deficiency, the precursors of IELps among CD4+CD8+ double-positive thymocytes exhibited increased apoptosis during agonist selection and impaired IELp differentiation and maturation. Together, our results elucidate BCL6 as a crucial transcription factor during the thymic development of CD8αα+ αβ IELs. Editor's summary: Intraepithelial lymphocytes (IELs) reside within the intestinal epithelium, where they regulate immune tolerance. Unconventional CD8αα+ αβ IELs are selected from thymic IEL precursors (IELps) after strong TCR signaling; however, the transcription factors governing this process of agonist selection are not well defined. Xing et al. found that mice lacking the transcription factor BCL6 in αβ T cells almost did not develop CD8αα+ αβ IELs. Thymic IELps up-regulated BCL6 after TCR stimulation, and BCL6 expression was required for their survival, differentiation, and maturation. These findings identify that BCL6 is required for the development of unconventional CD8αα+ αβ IELs during agonist selection. —Hannah Isles [ABSTRACT FROM AUTHOR]

Purpose: This study was designed to evaluate the effects of PD-1 inhibitor on lung tissue morphology and the immune system in a mouse model of radiation-induced lung injury (RILI) and to assess interactions between radiation therapy and PD-1 inhibition. Methods: Twenty C57BL/6 mice were divided randomly into four groups of five mice each. Mice were treated with an anti-mouse PD-1 monoclonal antibody, whole thorax irradiation, both or neither. Lung tissue morphology and pathological changes were assessed by hematoxylin-eosin staining; lung fibrosis was assessed by Masson staining and analysis of hydroxyproline; CD3+, CD4+, and CD8+ T lymphocytes in lung tissues were detected immunohistochemically; and the concentrations of transforming growth factor-β 1 (TGF-β 1) and interleukin-6 (IL-6) in lung tissue were evaluated by cytokine multiplex analysis. Results: Lung injury scores and indicators of pulmonary fibrosis were higher in mice administration whole thorax irradiation than in control mice. Inflammatory infiltrate scores, alveoli deformation scores, collagen volume fractions and hydroxyproline contents in lung tissues were all significantly higher in mice administered PD-1 inhibitor plus irradiation than in the other three groups. Similarly, the percentages of CD3+ and CD8+T cells and the concentrations of IL-6 and TGF-β 1 in lung tissue were significantly higher in mice treated with radiation and PD-1 inhibitor than in the other groups. However, PD-1 inhibitor and irradiation interacted significantly only in the elevation of TGF-β 1 level. Conclusion: Whole thorax X-ray irradiation in mice can cause pulmonary injury and fibrosis, which could be exacerbated by PD-1 inhibitors. Radiotherapy combined with PD-1 inhibitors may aggravate RILI by synergistically upregulating TGF-β 1 expression, thereby affecting the immune-inflammatory microenvironment in the lungs. [ABSTRACT FROM AUTHOR]

Summary: T helper 17 (Th17) cells specifically transcribe the Il17 and Il17f genes, which are localized in the same chromosome region, but the underlying mechanism is unclear. Here, we report a cis element that we previously named conserved noncoding sequence 2 (CNS2) physically interacted with both Il17 and Il17f gene promoters and was sufficient for regulating their selective transcription in Th17 cells. Targeted deletion of CNS2 resulted in impaired retinoic acid-related orphan receptor gammat (RORγt)-driven IL-17 expression in vitro. CNS2-deficient T cells also produced substantially decreased amounts of IL-17F. These cytokine defects were associated with defective chromatin remodeling in the Il17-Il17f gene locus, possibly because of effects on CNS2-mediated recruitment of histone-modifying enzymes p300 and JmjC domain-containing protein 3 (JMJD3). CNS2-deficient animals were also shown to be resistant to experimental autoimmune encephalomyelitis (EAE). Our results thus suggest that CNS2 is sufficient and necessary for Il17 and optimal Il17f gene transcription in Th17 cells. [ABSTRACT FROM AUTHOR]

Differentiating malignant from benign ascites often leads to confusion and an inability to exclude its multitude of causes in many patients. In the present study, T lymphocyte subsets and DNA ploidy in ascitic fluid were detected by flow cytometer. There were significant differences in T lymphocyte subsets between benign and malignant ascites. For malignant ascites, the sensitivity of DNA aneuploid is 75.6%, the specificity is 79.0%, and the accuracy is 77.6%. The results demonstrate that T lymphocyte subsets determination and DNA ploidy analysis can be used in the differential diagnosis between benign and malignant ascites. [ABSTRACT FROM AUTHOR]

T follicular helper (Tfh) cells play essential roles in regulating humoral immunity, especially germinal center reactions. However, how CD4+ T cells integrate the antigenic and costimulatory signals in Tfh cell development is still poorly understood. Here, we found that phorbol 12-myristate 13-acetate (PMA) + ionomycin (P+I) stimulation, together with interleukin-6 (IL-6), potently induce Tfh cell-like transcriptomic programs in vitro. The ERK kinase pathway was attenuated under P+I stimulation; ERK2 inhibition enhanced Tfh cell development in vitro and in vivo. We observed that inducible T cell costimulator (ICOS), but not CD28, lacked the ability to activate ERK, which was important in sustaining Tfh cell development. The transcription factor Zfp831, whose expression was repressed by ERK, promoted Tfh cell differentiation by directly upregulating the expression of the transcription factors Bcl6 and Tcf7. We have hence identified an ERK-Zfp831 axis, regulated by costimulation signaling, in critical regulation of Tfh cell development. [Display omitted] • PMA + ionomycin promote Tfh cell generation in vitro • ERK kinase pathway negatively regulates Tfh cell differentiation program • CD28 and ICOS signaling differentially regulate ERK during Tfh cell differentiation • Repressed by ERK, Zfp831 is a transcription factor that promotes Tfh cell development Tfh cell essentially regulates humoral immunity, but its differentiation process is not fully understood. Wan et al. reveal that ICOS and CD28 differentially regulate the ERK kinase pathway and ERK is Tfh-repressive. Repressed by ERK, the transcriptional factor Zfp831 promotes T follicular helper cell differentiation. [ABSTRACT FROM AUTHOR]

RORγt is the lineage-specific transcription factor for T helper 17 (Th17) cells whose upregulation in developing Th17 cells is critically regulated by interleukin-6 (IL-6) and TGF-β, the molecular mechanisms of which remain largely unknown. Here we identified conserved non-coding sequences (CNSs) 6 and 9 at the Rorc gene, essential for its expression during Th17 cell differentiation but not required for RORγt expression in innate lymphocytes and γδ T cells. Mechanistically, the IL-6-signal transducer and activator of transcription 3 (STAT3) axis appeared to be largely dependent on CNS9 and only partially on CNS6 in controlling RORγt expression and epigenetic activation of the Rorc locus. TGF-β alone was sufficient to induce RORγt expression in a CNS6- but not CNS9-dependent manner through CNS6 binding by SMAD proteins. Our study reveals an important synergistic mechanism downstream of IL-6 and TGF-β in regulation of RORγt expression and Th17 cell commitment via distinct cis -regulatory elements. • CNS6 and CNS9 are not required for RORγt expression in innate immune cells • Deficiency in CNS6 or CNS9 decreases Th17 cell differentiation and EAE disease • CNS9 and, to a lesser extent, CNS6 are required for IL-6-induced RORγt expression • CNS6, but not CNS9, is indispensable for TGF-β-induced RORγt expression IL-6 and TGF-β induce Th17 cell differentiation. Chang et al. demonstrate that these two cytokines initiate Th17 cell differentiation by inducing de novo Rorc transcription via the distinct conserved non-coding sequences CNS6 and CNS9. [ABSTRACT FROM AUTHOR]