ABSTRACT
Medullary thymic epithelial cells (mTECs) are essential for the establishment of self-tolerance in T cells. Promiscuous gene expression by a subpopulation of mTECs regulated by the nuclear protein Aire contributes to the display of self-genomic products to newly generated T cells. Recent reports have highlighted additional self-antigen-displaying mTEC subpopulations, namely Fezf2-expressing mTECs and a mosaic of self-mimetic mTECs including thymic tuft cells. In addition, a functionally different subset of mTECs produces chemokine CCL21, which attracts developing thymocytes to the medullary region. Here, we report that CCL21+ mTECs and Aire+ mTECs non-redundantly cooperate to direct self-tolerance to prevent autoimmune pathology by optimizing the deletion of self-reactive T cells and the generation of regulatory T cells. We also detect cooperation for self-tolerance between Aire and Fezf2, the latter of which unexpectedly regulates thymic tuft cells. Our results indicate an indispensable interplay among functionally diverse mTECs for the establishment of central self-tolerance.
Subject(s)
AIRE Protein , Central Tolerance , Epithelial Cells , Nerve Tissue Proteins , Thymus Gland , Transcription Factors , Animals , Epithelial Cells/metabolism , Thymus Gland/cytology , Thymus Gland/metabolism , Thymus Gland/immunology , Transcription Factors/metabolism , Transcription Factors/genetics , Mice , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Mice, Inbred C57BL , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Self ToleranceABSTRACT
Cation diffusion facilitators (CDFs) are a large family of divalent metal transporters with broad specificities that contribute to intracellular metal homeostasis and toxicity in bacterial pathogens. Streptococcus pyogenes (Group A Streptococcus [GAS]) expresses two homologous CDF efflux transporters, MntE and CzcD, which selectively transport Mn and Zn, respectively. We discovered that the MntE- and CzcD-deficient strains exhibited a marked decrease in the viability of macrophage-differentiated THP-1 cells and neutrophils. In addition, the viability of mice infected with both deficient strains markedly increased. Consistent with a previous study, our results suggest that MntE regulates the PerR-dependent oxidative stress response by maintaining intracellular Mn levels and contributing to the growth of GAS. The maturation and proteolytic activity of streptococcal cysteine protease (SpeB), an important virulence factor in GAS, has been reported to be abrogated by zinc and copper. Zn inhibited the maturation and proteolytic activity of SpeB in the culture supernatant of the CzcD-deficient strain. Furthermore, Mn inhibited SpeB maturation and proteolytic activity in a MntE-deficient strain. Since the host pathogenicity of the SpeB-deficient strain was significantly reduced, maintenance of intracellular manganese and zinc levels in the GAS via MntE and CzcD may not only confer metal resistance to the bacterium, but may also play an essential role in its virulence. These findings provide new insights into the molecular mechanisms of pathogenicity, which allow pathogens to survive under stressful conditions associated with elevated metal ion concentrations during host infection.
Subject(s)
Immune Evasion , Streptococcus pyogenes , Animals , Mice , Streptococcus pyogenes/metabolism , Metals/metabolism , Zinc/metabolism , Membrane Transport Proteins/metabolism , Cations, Divalent/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Gene Expression Regulation, BacterialABSTRACT
PURPOSE: The aim of this study was to evaluate the effects of inaccurate attenuation correction due to the misalignment between the computed tomography (CT)-based µ-map and the positron emission tomography (PET) data on a brain PET. METHODS: CT and PET scans were performed on a 3-dimension (3D) brain phantom, in which the grey matter region was filled with 18F-fluorodeoxyglucose (18F-FDG), and the skull region was filled with/without the bone-equivalent solution. The shifted PET images relative to the CT image were generated by the software-based translation of PET data in the cephalad/caudal and right directions, with a magnitude of the shift up to 30 mm and a step size of 5 mm. The regions of interest (ROIs) were drawn on the areas of the temporal lobes, parietal lobes, thalami, and cerebellums in the no-shifted image (reference). For each ROI, the radioactivity concentrations in the shifted images were compared with those of the reference. RESULTS: The errors in the radioactivity concentrations were increased with the increasing magnitude of the shift in all brain regions except for thalamus. For a 5 mm shift in the right direction, ± 10% errors were observed in the left/right temporal lobes. The accuracy of the radioactivity concentration in the temporal lobe was very sensitive to misalignment in the right directions. CONCLUSION: The misalignment between CT-based µ-map and PET data had larger effects on the surface regions of the brain rather than on deep brain structures.
