Dopamine D2 receptor on CD4+ T cells is protective against inflammatory responses and signs in a mouse model of rheumatoid arthritis.

BACKGROUND: Dopamine is a neurotransmitter and has been found to regulate lymphocytes by acting on dopamine receptors (DRs). CD4+ T cells express all the five subtypes of DRs, D1R to D5R. Although CD4+ T cells have been involved in pathogenesis of rheumatoid arthritis (RA), roles of DRs expressed on these cells in RA are poorly understood. This study determined whether D2R expressed on CD4+ T cells regulates inflammatory responses and signs in collagen type II (CII)-induced arthritis (CIA), a mouse model of RA. METHODS: DBA/1 mice and C57BL/6 mice with global D1r or D2r deficiency (D1r-/- or D2r-/-) or CD4+ T cell-specific D2r deletion (D2rfl/fl/CD4Cre) were used to prepare CIA model by intradermal injection of CII. D2R agonist sumanirole was intraperitoneally administered in CIA mice. CD4+ T cells obtained from CIA mice were exposed to sumanirole or/and D2R antagonist L-741,626 in vitro. Arthritic symptoms were assessed by clinical arthritis scores. Flow cytometric assay measured frequencies of CD4+ T cell subsets (Th1, Th2, Th17 and Treg cells). Expression of specific transcription factors for the CD4+ T cell subsets was tested by Western blot. Cytokine production was estimated by quantitative PCR and ELISA. RESULTS: CIA mice manifested a bias of CD4+ T cells towards Th1 and Th17 cells. D2r-/- CIA mice showed a stronger bias towards Th1 and Th17 phenotypes than CIA mice, while D1r-/- CIA mice did not show the changes. CD4+ T cell-specific D2r deletion exacerbated both the polarization towards Th1 and Th17 cells and the symptoms of arthritis. Sumanirole administration in CIA mice ameliorated the bias of CD4+ T cells towards Th1 and Th17 phenotypes as well as arthritic symptoms. Sumanirole treatment of in vitro CD4+ T cells obtained from CIA mice promoted the shift to Treg cells, and the effect of sumanirole was blocked by L-741,626. CONCLUSIONS: D2R expressed on CD4+ T cells is protective against imbalance between pro-inflammatory and anti-inflammatory T cells and arthritic symptoms in CIA.

Generation of Allogeneic CAR T Cells through Specific Degradation of the T Cell Antigen Receptor by E3 Ubiquitin Ligase Fusion Proteins.

Receptor downregulation is instrumental for many therapeutic interventions. Receptor knockout through gene-editing technologies is efficient but can introduce off-target mutations and chromothripsis. Regulation of gene expression at the protein level is a promising alternative. Here, we present results showing the targeted T cell antigen receptor (TCR) degradation using chimeric E3 fusion proteins that we call Receptor Targeting Chimeras (ReceptorTAC). We show that TCR degradation is dependent on enzymatically active, membrane-anchored E3 ligase variants. TCR specificity was achieved by direct fusion of an E3 domain to the CD3ζ transmembrane sequence. Jurkat and primary T cells stably expressing the ReceptorTAC constructs showed significantly reduced responses to TCR stimulation. We also used our ReceptorTAC technology to generate TCR-deficient, claudin18.2-specific CAR T cells, where the activity of the CAR was unaffected by the expression of the ReceptorTAC. These data indicate that our ReceptorTAC molecule can be used to generate allogeneic CAR T cells.

The Child Problematic Traits Inventory in China: A multiple informant-based validation study.

The aim of this study was to further test the reliability and validity of a newly developed instrument designed to assess psychopathic traits in children, the Child Problematic Traits Inventory (CPTI). Teachers and mothers of 686 approximately 6- to 12-year-old children (48.1% girls) completed the CPTI. Confirmatory factor analyses supported the proposed 3-factor structure of the CPTI teacher and parent versions and good to excellent internal consistency of the teacher- and mother-based CPTI scores were found. The validity of the teacher- and mother-based CPTI scores was supported by revealing the expected relations with conduct problems, hyperactivity, and various dimensions of temperament. In conclusion, the results suggest that the CPTI holds promise as a teacher- and parent-rated tool for assessing psychopathic traits in Chinese children, although more research is needed to see if these findings can be generalized to other Chinese samples and settings. (PsycINFO Database Record

Factor structure and construct validity of the Levenson Self-Report Psychopathy Scale (LSRP) in a sample of Chinese male inmates.

The current study examined the factor structure and convergent and discriminant validity of the Levenson Self-Report Psychopathy scale (LSRP) in Chinese male inmates (N = 437). The original 2-factor model, the revised 2-factor model, and the 3-factor model were tested through confirmatory factor analysis (CFA). Additionally, convergent and discriminant validity were examined via correlational and multiple linear regression analyses between LSRP factors and external criterion variables. Results showed that the 3-factor model fit the data better than the 2-factor model. The 3-factor model also showed reasonable convergent and discriminant validity. The findings were consistent with previous studies and suggested that the LSRP can be an effective self-report measure for assessing psychopathy in China. (PsycINFO Database Record

The factor structure and construct validity of the inventory of callous-unemotional traits in Chinese undergraduate students.

The current study assesses the factor structure and construct validity of the self-reported Inventory of Callous-Unemotional Traits (ICU) in 637 Chinese community adults (mean age = 25.98, SD = 5.79). A series of theoretical models proposed in previous studies were tested through confirmatory factor analyses. Results indicated that a shortened form that consists of 11 items (ICU-11) to assess callousness and uncaring factors has excellent overall fit. Additionally, correlations with a wide range of external variables demonstrated that this shortened form has similar construct validity compared to the original ICU. In conclusion, our findings suggest that the ICU-11 may be a promising self-report tool that could be a good substitute for the original form to assess callous-uncaring traits in adults.

Dopamine D2 Receptor Is Involved in Alleviation of Type II Collagen-Induced Arthritis in Mice.

Human and murine lymphocytes express dopamine (DA) D2-like receptors including DRD2, DRD3, and DRD4. However, their roles in rheumatoid arthritis (RA) are less clear. Here we showed that lymphocyte DRD2 activation alleviates both imbalance of T-helper (Th)17/T-regulatory (Treg) cells and inflamed symptoms in a mouse arthritis model of RA. Collagen-induced arthritis (CIA) was prepared by intradermal injection of chicken collagen type II (CII) in tail base of DBA/1 mice or Drd2 (-/-) C57BL/6 mice. D2-like receptor agonist quinpirole downregulated expression of proinflammatory Th17-related cytokines interleukin- (IL-) 17 and IL-22 but further upregulated expression of anti-inflammatory Treg-related cytokines transforming growth factor- (TGF-) ß and IL-10 in lymphocytes in vitro and in ankle joints in vivo in CIA mice. Quinpirole intraperitoneal administration reduced both clinical arthritis score and serum anti-CII IgG level in CIA mice. However, Drd2 (-/-) CIA mice manifested more severe limb inflammation and higher serum anti-CII IgG level and further upregulated IL-17 and IL-22 expression and downregulated TGF-ß and IL-10 expression than wild-type CIA mice. In contrast, Drd1 (-/-) CIA mice did not alter limb inflammation or anti-CII IgG level compared with wild-type CIA mice. These results suggest that DRD2 activation is involved in alleviation of CIA symptoms by amelioration of Th17/Treg imbalance.