Aire regulates medullary epithelial cell production of XCL1, a chemoattractant for XCR1-expressing thymic DCs whose presence in the medulla contributes to the generation of T reg cells.

How self-peptides displayed in the thymus contribute to the development of immunocompetent and self-protective T cells is largely unknown. In contrast, the role of thymic self-peptides in eliminating self-reactive T cells and thereby preventing autoimmunity is well established. A type of proteasome, termed thymoproteasome, is specifically expressed by thymic cortical epithelial cells (cTECs) and is required for the generation of optimal cellularity of CD8+ T cells. Here, we show that cTECs displayed thymoproteasome-specific peptide-MHC class I complexes essential for the positive selection of major and diverse repertoire of MHC class I-restricted T cells. CD8+ T cells generated in the absence of thymoproteasomes displayed a markedly altered T cell receptor repertoire that was defective in both allogeneic and antiviral responses. These results demonstrate that thymoproteasome-dependent self-peptide production is required for the development of an immunocompetent repertoire of CD8+ T cells.

JapanProteasomes are responsible for generating peptides presented by class I MHC molecules of the immune system. b5t, a recently identified proteasome component, is specifically expressed in thymic cortical epithelial cells (cTECs) and plays a pivotal role in generating an immunocompetent repertoire of class I MHC-restricted CD8 1 T cells. Here, we report that b5t is detectable in the thymus as early as E12.5 mouse embryos. We also found that b5t expression in cTECs was detectable in mice deficient for RelB or Rag2, indicating that b5t in cTECs is expressed in the absence of thymic medulla formation or thymocyte development beyond the CD4 À CD8 À stage. b5t expression in the embryonic thymus was not detectable in Foxn1-deficient nude mice, although its expression was not reduced in mice deficient for both CCR7 and CCR9, in which fetal thymus colonization by leukocytes is defective. These results indicate that b5t expression in cTECs is dependent on Foxn1 but independent of thymocyte crosstalk or thymic medulla formation.Keywords: b5t Á Thymic cortex Á Thymic cortical epithelial cell Á Thymoproteasome Supporting Information available online IntroductionProteasomes are multicatalytic protease complexes that are responsible for the regulation of proteolysis in eukaryotic cells and for the generation of antigenic peptides presented by class I MHC molecules [1]. The 20S proteasome is responsible for the proteolytic activity of the proteasome and is composed of 28 subunits (two a-rings with a1-a7 subunits and two b-rings with b1-b7 subunits). Among the subunits, b1, b2, and b5 are responsible for the proteolytic activity [2]. Interferon-g induces the production of a new set of catalytic subunits, b1i, b2i, and b5i, to replace their constitutive counterparts, b1, b2, and b5, thereby forming immunoproteasomes, which are proteasome complexes that possess altered proteolytic activity and participate in efficient antigen presentation and immune response [3]. We have recently identified a novel subunit of the 20S proteasome, b5t, which is specifically expressed in thymic cortical epithelial cells (cTECs) and plays a pivotal role in the development of CD8 1278T cells [4]. In cTECs, b5t, instead of b5 or b5i, is incorporated into the 20S proteasome together with b1i and b2i, thereby forming unique proteasome complexes termed thymoproteasomes [4]. We have reported evidence supporting the concept that cTECs display a thymoproteasome-specific spectrum of class I MHC-associated self-peptides that are required for the development of an immunocompetent repertoire of CD8 1 T cells [5].Thus, b5t expressed by cTECs is indispensable for the development of the self-protective adaptive immune system [6]. The notion that b5t is specifically expressed in cTECs is based on the following findings: (i) the expression of b5t in various adult mouse organs was specifically detected in the thymus by RNA blot analysis and immunoblot analysis [4]; (ii) b5t in adult mouse thymus was specifically detected in Ly51 1 cells in the immunohistological a...

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Background and Purpose-Recent studies have shown that the cellular immune response in the development of vascular remodeling modulates the resulting pathological alterations. We show that hypoxia-inducible factor 1 (Hif-1) (specifically expressed in T cells) is involved in the immune response to vascular remodeling that accompanies arteriosclerosis. Methods and Results-To study the role of T cells in the development of vascular remodeling, femoral arterial injury induced by an external vascular polyethylene cuff was examined in mice lacking Hif-1 (specifically in T cells). We found that cuff placement caused prominent neointimal hyperplasia of the femoral artery in Hif-1-(T-cell)-deficient mice compared with that in control mice and that infiltration of inflammatory cells at the adventitia was markedly increased in the mutant mice. Studies to clarify the mechanism of augmented vascular remodeling in the mutant mice showed enhanced production of cytokines by activated T cells and augmented antibody production in response to a T-dependent antigen in the mutant mice. T he vascular response to mechanical arterial injury involved in arteriosclerosis or in-stent restenosis leads to neointimal formation and inward remodeling. Recent studies have shown that the immune system plays an important role in the development of vascular remodeling in response to arterial injury. 1 Studies 2-4 in mice have shown that arterial injury is associated with local accumulation of antibodies, and mice lacking functional T and B cells exhibit increased neointima formation, indicating that adaptive immune responses to neoantigens in the damaged tissue modulate the vascular remodeling. During the development of vascular remodeling, a hypoxic microenvironment accompanying arteriosclerosis or stent-mediated overdistention in the injured vascular region is thought to be one of the factors modulating proliferation of myofibroblasts and increased matrix synthesis in the adventitial region. 5 It has also been reported that hypoxia accelerates the progression of atherosclerosis 6,7 and modulates vascular remodeling after arterial injury. 8 Several studies 10,11 have shown evidence of hypoxia within the arterial wall in atherosclerosis in an animal model 9 and in human disease. Adaptation to low oxygen tension in local tissues is important for activities of immune cells, because immune cells are often exposed to different oxygen tensions that markedly affect cellular metabolism as they survey different tissue microenvironments. 12 Hypoxia-inducible factor 1 (Hif-1) is a transcription factor that regulates gene expression in response to hypoxia; it is composed of heterodimers of an oxygensensitive ␣ subunit and a constitutively expressed ␤ subunit (also known as arylhydrocarbon receptor nuclear translocator). Hif-1␣ regulates the expressions of genes in response to hypoxia to maintain physiological oxygen homeostasis. 14 In addition to hypoxic stabilization of Hif-1␣, resulting in upregulation of Hif-1␣ functions, several factors relevant to infla...

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Synonymous codon usage bias is an inevitable phenomenon in organismic taxa across the three domains of life. Though the frequency of codon usage is not equal across species and within genome in the same species, the phenomenon is non random and is tissue-specific. Several factors such as GC content, nucleotide distribution, protein hydropathy, protein secondary structure, and translational selection are reported to contribute to codon usage preference. The synonymous codon usage patterns can be helpful in revealing the expression pattern of genes as well as the evolutionary relationship between the sequences. In this study, synonymous codon usage bias patterns were determined for the evolutionarily close proteins of albumin superfamily, namely, albumin, α-fetoprotein, afamin, and vitamin D-binding protein. Our study demonstrated that the genes of the four albumin superfamily members have low GC content and high values of effective number of codons (ENC) suggesting high expressivity of these genes and less bias in codon usage preferences. This study also provided evidence that the albumin superfamily members are not subjected to mutational selection pressure.

BackgroundCarica papaya leaves have been used for traditional treatment of dengue fever and have been reported to exhibit an immunomodulatory activity by affecting the level of cytokine production in vitro and in vivo. Due to the lack of adequate in vivo evidence in dengue disease model, the present study was initiated to screen and identify the cytokines affected by freeze-dried C. papaya leaf juice (FCPLJ) treatment in AG129 mice infected with DEN-2 dengue virus.MethodsThe AG129 mice were fed orally with FCPLJ for 3 consecutive days after 24 h of dengue virus inoculation. Plasma cytokines were screened by using ProcartaPlex immunoassay. The gene expression in the liver was analyzed by using RT2 Profiler PCR Array.ResultsThe results showed that FCPLJ treatment has increased the plasma CCL2/MCP-1 level during peak of viremia. Gene expression study has identified 8 inflammatory cytokine genes which were downregulated in the liver of infected AG129 mice treated with FCPLJ. The downregulated inflammatory cytokine genes were CCL6/MRP-1, CCL8/MCP-2, CCL12/MCP-5, CCL17/TARC, IL1R1, IL1RN/IL1Ra, NAMPT/PBEF1 and PF4/CXCL4.ConclusionThe findings indicated the possible immunomodulatory role of FCPLJ during dengue virus infection in AG129 mice.Electronic supplementary materialThe online version of this article (10.1186/s12906-019-2438-3) contains supplementary material, which is available to authorized users.