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A major breakthrough in cancer treatment occurred with the development of strategies that overcome T-cell tolerance toward tumor cells. These approaches enhance antitumor immunity by overcoming mechanisms that are normally in place to prevent autoimmunity but simultaneously prevent rejection of tumor cells. Although tolerance mechanisms that restrict antitumor immunity take place both in the thymus and periphery, only immunotherapies that target peripheral tolerance mechanisms occurring outside of the thymus are currently available. We review here recent gains in our understanding of how thymic tolerance mediated by the autoimmune regulator (Aire) impedes antitumor immunity. It is now clear that transient depletion of Aire-expressing cells in the thymus can be achieved with RANKL blockade. Finally, we discuss key findings that support the repurposing of anti-RANKL as a cancer immunotherapy with a unique mechanism of action.

CXCL17 is a homeostatic chemokine in the mucosa known to chemoattract dendritic cells and macrophages but can also be expressed elsewhere under inflammatory conditions. Cxcl17-/- mice have lower numbers of macrophages or dendritic cells in mucosal tissues. CXCL17 is also able to chemoattract suppressor myeloid cells that can recruit regulatory T cells. To explore a possible role of Cxcl17 in T cells, we studied T cell populations from Cxcl17-/- or wild-type (WT) littermate mice. Cxcl17-/- mice have higher numbers of CD4+ and CD8+ T cells in spleen and lymph nodes (LNs). Upon activation, they produce higher levels of several proinflammatory cytokines and chemokines. Furthermore, a Cxcl17-/- mouse developed exacerbated disease in a T cell-dependent model of experimental autoimmune encephalomyelitis (EAE). By 18 days after immunization with myelin oligodendrocyte peptide, only 44% of Cxcl17-/- mice were still alive vs. 90% for WT mice. During EAE, Cxcl17-/- mice exhibited higher numbers of lymphoid and myeloid cells in spleen and LNs, whereas they had less myeloid cell infiltration in the CNS. Cxcl17-/- mice also had higher levels of some inflammatory cytokines in serum, suggesting that they may be involved in the poor survival of these mice. Abnormal T cell function may reflect altered myeloid cell migration, or it could be due to altered T cell development in the thymus. We conclude that CXCL17 is a novel factor regulating T cell homeostasis and function.

Abstract Background Thymus has a pivotal role in combating infectious diseases. Although some reviews have been published about its critical role in COVID-19, there is not enough research. In this study, the size and density of thymus related to computed tomography pulmonary severity score (CT-SS) were researched. Results A total of 196 patients were analyzed with a mean age of 52.54 ± 18.78 years; 97 (49.5%) of them were RT-PCR (−) and 99 (50.5%) were RT-PCR (+). Within RT-PCR (+) group 62 (62.6%) of them had pneumonia with a mean CT-SS of 9.37 ± 8.83; within RT-PCR (−) group 20 (20.6%) of them had pneumonia with the mean CT-SS of 12.00 ± 10.18. CT-SS had moderate negative correlation with thymus volume and thymus maximum diameter in patients having nodular-type thymus (R = −0.591, P = 0.02; R = −0.515, P = 0.049, respectively). Homogenous fat infiltration was more commonly seen in RT-PCR (−) group while reticular and nodular types were commonly seen in RT-PCR (+) group (p = 0.015). The mean volume and maximum diameter of thymus were statistically significantly higher in RT-PCR (+) group (p = 0.027 and p = 0.048, respectively). Conclusion This study showed the higher thymic volume and maximum diameter and more involution in COVID-19 patients. CT-SS had a moderate negative correlation with thymus volume and thymus maximum diameter. Pneumonia was more frequent in COVID patients, but mean CT-SS of the non-COVID cases was higher.

Chronic obstructive pulmonary disease is an inflammatory lung disease characterized by chronic bronchitis and emphysema. Our previous study revealed that testosterone depletion induced T cell infiltration in the lungs and aggravated pulmonary emphysema in orchiectomized (ORX) mice exposed to porcine pancreatic elastase (PPE). However, the association between T cell infiltration and emphysema remains unclear. The aim of this study was to determine whether thymus and T cells are involved in the exacerbation of PPE-induced emphysema in ORX mice. The weight of thymus gland in ORX mice was significantly greater than that of sham mice. The pretreatment of anti-CD3 antibody suppressed PPE-induced thymic enlargement and T cell infiltration in the lungs in ORX mice, resulting in improved expansion of the alveolar diameter, a marker of emphysema exacerbation. These results suggest that increased thymic function due to testosterone deficiency and the associated increased pulmonary infiltration of T cells may trigger the development of emphysema.

Cyclophosphamide (CP) is a chemotherapeutic drug that has a harmful effect on the immune system. Growth hormone (GH) is a peptide hormone that can enhance thymic functions in cases of immunosuppression. Therefore, the present study was performed to study the possible protective effect of growth hormone on cyclophosphamide-induced changes in the rat thymus gland. Sixty-four adult male albino rats were used and divided into three main groups. Group I (Control group). Group II (CP group) received 200 mg/kg body weight CP by a single intra-peritoneal injection. Group III (CP& GH group) received GH in a dose of 2 mg/kg body weight/day by subcutaneous injection starting 5 days before cyclophosphamide injection till the end of the experiment. Administration of CP (Group II) resulted in marked histopathological changes in thymus. Thymic cortex showed depletion of thymoblasts. There was a decrease in CD34 immune positively stained stem cells and an increase in CD68 immune positively stained macrophages. Ultrastructurally, thymoblasts were markedly degenerated and the most of epithelial reticular cells were vacuolated. Administration of GH (group III) showed preservation of the histological structure of the thymus. In conclusion, growth hormone could protect against cyclophosphamide induced thymic damage. [ABSTRACT FROM AUTHOR]

We investigated the presence of radiographic thymus variants using a scoring system and examined their association with clinical and immunological features in primary Sjögren's syndrome (pSS) and polymyositis/dermatomyositis (PM/DM) patients. Cases of 72 patients with pSS and 47 with PM/DM were randomly selected from all visitors to our department who received chest CT scanning, excluding those with thymoma or thymic cyst, or age <30 years. We quantitatively interpreted and assessed thymus size and attenuation score in axial CT images. Thymic enlargement was identified in 16 (22.2%) pSS and 14 (29.8%) PM/DM patients. A thymus attenuation score ≥ 2 was seen in 11 (15.3%) pSS and 9 (19.1%) PM/DM patients. Thymic enlargement showed a significant association with the titre of rheumatoid factor in PM/DM patients. Thymic enlargement and score showed a significant association with body weight in pSS patients. Radiographic thymus variants are often observed in pSS and PM/DM patients, particularly in cases of PM/DM, and may suggest the role of an abnormal immune response in their pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract Background Chest MRI is a useful diagnostic modality for the evaluation of anterior mediastinal lesions but the outcomes of anterior mediastinal cystic lesions diagnosed on chest MRI are unclear. Methods In this multicenter retrospective study, patients who underwent contrast-enhanced chest MRI in two tertiary centers to assess anterior mediastinal cystic lesions were included after excluding overt solid tumors and thymic hyperplasia. Anterior mediastinal cystic lesions were classified into two categories: probable (simple) cyst or indeterminate lesion (complex cyst). Size and imaging features of lesions during follow-up were evaluated and clinical outcomes were assessed. Results A total of 204 patients (mean age, 59 ± 11 years; M:F = 111:93) were studied; 186 (91.2%) were classified as probable cysts and 18 (8.8%) as indeterminate lesions on MRI. Among patients with probable cysts and more than 2 years of follow-up, lesion size was unchanged in 39.6% (36/91), decreased in 16.5% (15/91), and fluctuated in 8.8% (8/91). All patients who underwent surgery were confirmed cysts. None developed mural nodules or irregular wall thickening, suspicious for malignancy during follow-up. In patients with indeterminate lesions, 16.7% (3/18) had pathologically confirmed thymoma and 44.4% (8/18) had proven cysts. Follow-up numbers and intervals after MRI in patients with probable cysts were variable among physicians and institutions in clinical practice (p

The developmental programs that generate a broad repertoire of regulatory T cells (Treg cells) able to respond to both self antigens and non-self antigens remain unclear. Here we found that mature Treg cells were generated through two distinct developmental programs involving CD25+ Treg cell progenitors (CD25+ TregP cells) and Foxp3lo Treg cell progenitors (Foxp3lo TregP cells). CD25+ TregP cells showed higher rates of apoptosis and interacted with thymic self antigens with higher affinity than did Foxp3lo TregP cells, and had a T cell antigen receptor repertoire and transcriptome distinct from that of Foxp3lo TregP cells. The development of both CD25+ TregP cells and Foxp3lo TregP cells was controlled by distinct signaling pathways and enhancers. Transcriptomics and histocytometric data suggested that CD25+ TregP cells and Foxp3lo TregP cells arose by coopting negative-selection programs and positive-selection programs, respectively. Treg cells derived from CD25+ TregP cells, but not those derived from Foxp3lo TregP cells, prevented experimental autoimmune encephalitis. Our findings indicate that Treg cells arise through two distinct developmental programs that are both required for a comprehensive Treg cell repertoire capable of establishing immunotolerance.

Stress can impair T cell-mediated immunity. To determine if infants with high stress responses had deficits in T-cell mediated immunity, we examined the association of pain-induced cortisol responsiveness with thymic function and vaccine responses in infants. This study was performed among 306 (male = 153 and female = 153) participants of a randomized, controlled trial examining the effect of neonatal vitamin A supplementation on immune function in Bangladesh (NCT01583972). Salivary cortisol was measured before and 20 min after a needle stick (vaccination) at 6 weeks of age. The thymic index (TI) was determined by ultrasonography at 1, 6, 10 and 15 weeks. T-cell receptor excision circle and blood T-cell concentrations were measured at 6 and 15 weeks. Responses to Bacillus Calmette-Guérin (BCG), tetanus toxoid, hepatitis B virus and oral poliovirus vaccination were assayed at 6 and 15 weeks. Cortisol responsiveness was negatively associated with TI at all ages (p

Here, we investigate the role of RelB in the regulation of genes which were identified to be induced in an aryl hydrocarbon receptor (AhR)-dependent manner and critically involved in regulation of immune responses. We analyzed the expression of genes of the AhR gene battery, cytokines, and immune regulatory enzymes in bone marrow-derived macrophages (BMM) and thymus of B6 wildtype (wt) mice and RelB knockout (RelB-/-) mice after treatment with various AhR ligands. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced expression of indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2 was significantly repressed in thymus of RelB-/- mice but not in BMM derived from RelB-/- mice. Interestingly, the induced and basal expression of the cytokines interleukin (IL)-17A, IL-22, and CCL20 required the functional expression of RelB. The RelB-dependent expression of CCL20 was induced by the AhR ligands TCDD and 6-formylindolo[3,2-b]carbazole (FICZ), whereas indole-3-carbinol (I3C) suppressed CCL20 in lipopolysaccharide (LPS)-activated wt BMM. The LPS-induced expression of IL-6 and IL-10 was enhanced by TCDD and FICZ, whereas I3C significantly suppressed these cytokines in BMM. The exposure to FICZ led to higher increases of IL-17A and IL-22 mRNA compared to the effect of TCDD or I3C in thymus of wt mice. On the other hand, TCDD was the strongest inducer of CYP1A1, AhR Repressor (AhRR), and IDO2. In summary, these findings provide evidence for the important role of RelB in the transcriptional regulation of cytokines and enzymes induced by AhR ligands.

Regulatory T cells (Tregs) are an immunosuppressive population that are identified based on the stable expression of the fate-determining transcription factor forkhead box P3 (Foxp3). Tregs can be divided into distinct subsets based on whether they developed in the thymus (tTregs) or in the periphery (pTregs). Whether there are unique functional roles that distinguish pTregs and tTregs remains largely unclear. To elucidate these functions, efforts have been made to specifically identify and modify individual Treg subsets. Deletion of the conserved non-coding sequence (CNS)1 in the Foxp3 locus leads to selective impairment of pTreg generation without disrupting tTreg generation in the C57BL/6J background. Using CRISPR-Cas9 genome editing technology, we removed the Foxp3 CNS1 region in the non-obese diabetic (NOD) mouse model of spontaneous type 1 diabetes mellitus (T1D) to determine if pTregs contribute to autoimmune regulation. Deletion of CNS1 impaired in vitro induction of Foxp3 in naïve NOD CD4+ T cells, but it did not alter Tregs in most lymphoid and non-lymphoid tissues analyzed except for the large intestine lamina propria, where a small but significant decrease in RORγt+ Tregs and corresponding increase in Helios+ Tregs was observed in NOD CNS1-/- mice. CNS1 deletion also did not alter the development of T1D or glucose tolerance despite increased pancreatic insulitis in pre-diabetic female NOD CNS1-/- mice. Furthermore, the proportions of autoreactive Tregs and conventional T cells (Tconvs) within pancreatic islets were unchanged. These results suggest that pTregs dependent on the Foxp3 CNS1 region are not the dominant regulatory population controlling T1D in the NOD mouse model.

Arising within the neural tube between the cranial and trunk regions of the body axis, the vagal neural crest shares interesting similarities in its migratory routes and derivatives with other neural crest populations. However, the vagal neural crest is also unique in its ability to contribute to diverse organs including the heart and enteric nervous system. This review highlights the migratory routes of the vagal neural crest and compares them across multiple vertebrates. We also summarize recent advances in understanding vagal neural crest ontogeny and discuss the contribution of this important neural crest population to the cardiovascular system and endoderm-derived organs, including the thymus, lungs and pancreas.

Various subsets of invariant natural killer T (iNKT) cells with different cytokine productions develop in the mouse thymus, but the factors driving their differentiation remain unclear. Here we show that hypomorphic alleles of Zap70 or chemical inhibition of Zap70 catalysis leads to an increase of IFN-γ-producing iNKT cells (NKT1 cells), suggesting that NKT1 cells may require a lower TCR signal threshold. Zap70 mutant mice develop IL-17-dependent arthritis. In a mouse experimental arthritis model, NKT17 cells are increased as the disease progresses, while NKT1 numbers negatively correlates with disease severity, with this protective effect of NKT1 linked to their IFN-γ expression. NKT1 cells are also present in the synovial fluid of arthritis patients. Our data therefore suggest that TCR signal strength during thymic differentiation may influence not only IFN-γ production, but also the protective function of iNKT cells in arthritis.

Although the thymus has long been recognized as a key organ for T cell selection, the intricate details linking these selection events to human autoimmunity have been challenging to decipher. Over the last two decades, there has been rapid progress in understanding the role of thymic tolerance mechanisms in autoimmunity through genetics. Here we review some of the recent progress in understanding key thymic tolerance processes that are critical for preventing autoimmune disease.

T cell-antigen receptor (TCR) signaling requires the sequential activities of the kinases Lck and Zap70. Upon TCR stimulation, Lck phosphorylates the TCR, thus leading to the recruitment, phosphorylation, and activation of Zap70. Lck binds and stabilizes phosho-Zap70 by using its SH2 domain, and Zap70 phosphorylates the critical adaptors LAT and SLP76, which coordinate downstream signaling. It is unclear whether phosphorylation of these adaptors occurs through passive diffusion or active recruitment. We report the discovery of a conserved proline-rich motif in LAT that mediates efficient LAT phosphorylation. Lck associates with this motif via its SH3 domain, and with phospho-Zap70 via its SH2 domain, thereby acting as a molecular bridge that facilitates the colocalization of Zap70 and LAT. Elimination of this proline-rich motif compromises TCR signaling and T cell development. These results demonstrate the remarkable multifunctionality of Lck, wherein each of its domains has evolved to orchestrate a distinct step in TCR signaling.

The thymus is responsible for generating a diverse yet self-tolerant pool of T cells1. Although the thymic medulla consists mostly of developing and mature AIRE+ epithelial cells, recent evidence has suggested that there is far greater heterogeneity among medullary thymic epithelial cells than was previously thought2. Here we describe in detail an epithelial subset that is remarkably similar to peripheral tuft cells that are found at mucosal barriers3. Similar to the periphery, thymic tuft cells express the canonical taste transduction pathway and IL-25. However, they are unique in their spatial association with cornified aggregates, ability to present antigens and expression of a broad diversity of taste receptors. Some thymic tuft cells pass through an Aire-expressing stage and depend on a known AIRE-binding partner, HIPK2, for their development. Notably, the taste chemosensory protein TRPM5 is required for their thymic function through which they support the development and polarization of thymic invariant natural killer T cells and act to establish a medullary microenvironment that is enriched in the type 2 cytokine, IL-4. These findings indicate that there is a compartmentalized medullary environment in which differentiation of a minor and highly specialized epithelial subset has a non-redundant role in shaping thymic function.

The development of T cell tolerance in the thymus requires the presentation of host proteins by multiple antigen-presenting cell (APC) types. However, the importance of transferring host antigens from transcription factor AIRE-dependent medullary thymic epithelial cells (mTECs) to bone marrow (BM) APCs is unknown. We report that antigen was primarily transferred from mTECs to CD8α+ dendritic cells (DCs) and showed that CD36, a scavenger receptor selectively expressed on CD8α+ DCs, mediated the transfer of cell-surface, but not cytoplasmic, antigens. The absence of CD8α+ DCs or CD36 altered thymic T cell selection, as evidenced by TCR repertoire analysis and the loss of allo-tolerance in murine allogeneic BM transplantation (allo-BMT) studies. Decreases in these DCs and CD36 expression in peripheral blood of human allo-BMT patients correlated with graft-versus-host disease. Our findings suggest that CD36 facilitates transfer of mTEC-derived cell-surface antigen on CD8α+ DCs to promote tolerance to host antigens during homeostasis and allo-BMT.

Background: Thymus has a pivotal role in combating infectious diseases. Although some reviews have been published about its critical role in COVID-19, there is not enough research. In this study, the size and density of thymus related to computed tomography pulmonary severity score (CT-SS) were researched. Results: A total of 196 patients were analyzed with a mean age of 52.54 ± 18.78 years; 97 (49.5%) of them were RT-PCR (−) and 99 (50.5%) were RT-PCR (+). Within RT-PCR (+) group 62 (62.6%) of them had pneumonia with a mean CT-SS of 9.37 ± 8.83; within RT-PCR (−) group 20 (20.6%) of them had pneumonia with the mean CT-SS of 12.00 ± 10.18. CT-SS had moderate negative correlation with thymus volume and thymus maximum diameter in patients having nodular-type thymus (R = −0.591, P = 0.02; R = −0.515, P = 0.049, respectively). Homogenous fat infiltration was more commonly seen in RT-PCR (−) group while reticular and nodular types were commonly seen in RT-PCR (+) group (p = 0.015). The mean volume and maximum diameter of thymus were statistically significantly higher in RT-PCR (+) group (p = 0.027 and p = 0.048, respectively). Conclusion: This study showed the higher thymic volume and maximum diameter and more involution in COVID-19 patients. CT-SS had a moderate negative correlation with thymus volume and thymus maximum diameter. Pneumonia was more frequent in COVID patients, but mean CT-SS of the non-COVID cases was higher. [ABSTRACT FROM AUTHOR]

Objective: To study the clinicopathological features, treatment method and prognosis of intrathyroid thymic carcinoma (ITTC), and to strengthen the clinicans’understandings of the disease. Methods: The clinical manifestations of one patient with ITTC were observed. The general morphology of the tumor was observed with naked eyes, laboratory examination and imaging examination were performed, the fine needle aspiration cytology of the thyroid tumor was observed, the morphology of the tumor tissue was observed under light microscope, immunohistochemistry staining and in situ hybridization were performed in the tumor tissue, and the patient was followed up 3 and 11 months after operation；the relevant literatures were reviewed. Results: The main clinical manifestation of the ITTC patient was a slightly hard mass in the thyroid. The fine needle aspiration cytology results showed that the tumor cells showed a threedimensional structure, and the prominent nucleoli could be seen in some cells. The histology results showed that the cancer cells were nest like or island like and differentiated into the squamous cells；the fibrous tissue proliferated accompanying with lymphocyte infiltration around the cancer cells and the right cervical lymph node metastasis. The immunophenotype detection results showed that the cancer cells expressed CD117, CD5 and P63, but didn’t express TdT and TTF-1, EBER-ISH (－). The pathological diagnosis was ITTC accompanying with cervical lymph node metastasis. No recurrence or metastasis was found on CT 3 and 11 months after operation. Conclusion: ITTC has low malignancy degree, which can relapse and metastasize, and combined with surgery and radiotherapy, the prognosis of the patients is good. [ABSTRACT FROM AUTHOR]

Introduction. Bone sarcomas, as rare tumour types, constitute only about 1% of malignant tumours. The treatment process is an additional burden on the human body, especially at a young age. The surgery has a long-term effect on the patient's mobility and requires great effort and motivation to regain physical fitness. The discomfort resulting from having a persistent thymus gland makes it significantly more difficult for patients to return to their precancerous state. Aim. The aim of this study is to diagnose the patient's health problems resulting from the presence of persistent thymus gland and a history of oncological treatment for osteosarcoma, together with the presentation of measures to improve functioning in daily life. Material and methods. The research method of the individual case study and the research techniques used were: interview, observation, measurement and analysis of medical records. Additionally, 9 scales were used, which allowed for a comprehensive assessment of the patient's health status. Results and summary. The following health problems were identified: dyspnoea, cough, muscle weakness, pain in the spine and left lower limb, dizziness and fatigue. Close cooperation of the interdisciplinary team, the patient and her relatives and a holistic approach is the key to developing an effective care plan together with tailoring such therapeutic and caring activities that increase the patient's comfort of life. [ABSTRACT FROM AUTHOR]

Thymic dendritic cells (tDCs) play an important role in central tolerance by eliminating self-reactive thymocytes or differentiating them to regulatory T (Treg) cells. However, the molecular and cellular mechanisms underlying these functions are not completely understood. We found that mouse tDCs undergo maturation following cognate interaction with self-reactive CD4+ thymocytes and that this maturation is dependent on CD40 signaling. Ablation of CD40 expression in tDCs resulted in a significant reduction in the number of Treg cells in association with a significant reduction in the number of mature tDCs. In addition, CD40-deficient DCs failed to fully mature upon cognate interaction with CD4+ thymocytes in vitro and failed to differentiate them into Treg cells to a sufficient number. These findings suggest that tDCs mature and potentiate Treg cell development in feedback response to self-reactive CD4+ thymocytes.

Although autoimmune disorders are a significant source of morbidity and mortality in older individuals, the mechanisms governing age-associated increases in susceptibility remain incompletely understood. Central T cell tolerance is mediated through presentation of self-antigens by cells constituting the thymic microenvironment, including epithelial cells, dendritic cells, and B cells. Medullary thymic epithelial cells (mTECs) and B cells express distinct cohorts of self-antigens, including tissue-restricted self-antigens (TRAs), such that developing T cells are tolerized to antigens from peripheral tissues. We find that expression of the TRA transcriptional regulator Aire, as well as Aire-dependent genes, declines with age in thymic B cells in mice and humans and that cell-intrinsic and cell-extrinsic mechanisms contribute to the diminished capacity of peripheral B cells to express Aire within the thymus. Our findings indicate that aging may diminish the ability of thymic B cells to tolerize T cells, revealing a potential mechanistic link between aging and autoimmunity.

AIRE is a well-established master regulator of central tolerance. It plays an essential role in driving expression of tissue-specific antigens in the thymus and shaping the development of positively selected T-cells. Humans and mice with compromised or absent AIRE function have markedly variable phenotypes that include a range of autoimmune manifestations. Recent evidence suggests that this variability stems from cooperation of autoimmune susceptibilities involving both central and peripheral tolerance checkpoints. Here we discuss the broadening understanding of the factors that influence Aire expression, modify AIRE function, and the impact and intersection of AIRE with peripheral immunity. This rapidly expanding body of knowledge will force a reexamination of the definition and clinical management of APS-1 patients as well as provide a foundation for the development of immunomodulatory strategies targeting central tolerance.

It is now established that Bcl11b specifies T cell fate. Here, we show that in developing T cells, the Bcl11b enhancer repositioned from the lamina to the nuclear interior. Our search for factors that relocalized the Bcl11b enhancer identified a non-coding RNA named ThymoD (thymocyte differentiation factor). ThymoD-deficient mice displayed a block at the onset of T cell development and developed lymphoid malignancies. We found that ThymoD transcription promoted demethylation at CTCF bound sites and activated cohesin-dependent looping to reposition the Bcl11b enhancer from the lamina to the nuclear interior and to juxtapose the Bcl11b enhancer and promoter into a single-loop domain. These large-scale changes in nuclear architecture were associated with the deposition of activating epigenetic marks across the loop domain, plausibly facilitating phase separation. These data indicate how, during developmental progression and tumor suppression, non-coding transcription orchestrates chromatin folding and compartmentalization to direct with high precision enhancer-promoter communication.

iNKT cells are a unique lineage of T cells that recognize glycolipid presented by CD1d. In the thymus, they differentiate into iNKT1, iNKT2 and iNKT17 effector subsets, characterized by preferential expression of Tbet, Gata3 and ROR-γt and production of IFN-γ, IL-4 and IL-17, respectively. We demonstrate that the transcriptional regulator Runx1 is essential for the generation of ROR-γt expressing iNKT17 cells. PLZF-cre Runx1 cKO mice lack iNKT17 cells in the thymus, spleen and liver. Runx1-deficient iNKT cells have altered expression of several genes important for iNKT17 differentiation, including decreased expression of IL-7Rα, BATF and c-Maf and increased expression of Bcl11b and Lef1. However, reduction of Lef1 expression or introduction of an IL-7Rα transgene is not sufficient to correct the defect in iNKT17 differentiation, demonstrating that Runx1 is a key regulator of several genes required for iNKT17 differentiation. Loss of Runx1 leads to a severe decrease in iNKT cell numbers in the thymus, spleen and liver. The decrease in cell number is due to a combined decrease in proliferation at Stage 1 during thymic development and increased apoptosis. Thus, we describe a novel role of Runx1 in iNKT cell development and differentiation, particularly in orchestrating iNKT17 differentiation.

Varicella zoster virus (VZV) causes varicella during acute infection and establishes latency in the sensory ganglia. Reactivation of VZV results in herpes zoster, a debilitating and painful disease. It is believed that VZV reactivates due to a decline in cell-mediated immunity; however, the roles that CD4 versus CD8 T cells play in the prevention of herpes zoster remain poorly understood. To address this question, we used a well-characterized model of VZV infection where rhesus macaques are intrabronchially infected with the homologous simian varicella virus (SVV). Latently infected rhesus macaques were thymectomized and depleted of either CD4 or CD8 T cells to induce selective senescence of each T cell subset. After T cell depletion, the animals were transferred to a new housing room to induce stress. SVV reactivation (viremia in the absence of rash) was detected in three out of six CD8-depleted and two out of six CD4-depleted animals suggesting that both CD4 and CD8 T cells play a critical role in preventing SVV reactivation. Viral loads in multiple ganglia were higher in reactivated animals compared to non-reactivated animals. In addition, reactivation results in sustained transcriptional changes in the ganglia that enriched to gene ontology and diseases terms associated with neuronal function and inflammation indicative of potential damage as a result of viral reactivation. These studies support the critical role of cellular immunity in preventing varicella virus reactivation and indicate that reactivation results in long-lasting remodeling of the ganglia transcriptome.

Transforming growth factor β (TGF-β) is a pleiotropic cytokine involved in both suppressive and inflammatory immune responses. After 30 years of intense study, we have only begun to elucidate how TGF-β alters immunity under various conditions. Under steady-state conditions, TGF-β regulates thymic T-cell selection and maintains homeostasis of the naïve T-cell pool. TGF-β inhibits cytotoxic T lymphocyte (CTL), Th1-, and Th2-cell differentiation while promoting peripheral (p)Treg-, Th17-, Th9-, and Tfh-cell generation, and T-cell tissue residence in response to immune challenges. Similarly, TGF-β controls the proliferation, survival, activation, and differentiation of B cells, as well as the development and functions of innate cells, including natural killer (NK) cells, macrophages, dendritic cells, and granulocytes. Collectively, TGF-β plays a pivotal role in maintaining peripheral tolerance against self- and innocuous antigens, such as food, commensal bacteria, and fetal alloantigens, and in controlling immune responses to pathogens.

Studies of human T cell development require robust model systems that recapitulate the full span of thymopoiesis, from hematopoietic stem and progenitor cells (HSPCs) through to mature T cells. Existing in vitro models induce T cell commitment from human HSPCs; however, differentiation into mature CD3+TCR-αβ+ single-positive CD8+ or CD4+ cells is limited. We describe here a serum-free, artificial thymic organoid (ATO) system that supports efficient and reproducible in vitro differentiation and positive selection of conventional human T cells from all sources of HSPCs. ATO-derived T cells exhibited mature naive phenotypes, a diverse T cell receptor (TCR) repertoire and TCR-dependent function. ATOs initiated with TCR-engineered HSPCs produced T cells with antigen-specific cytotoxicity and near-complete lack of endogenous TCR Vβ expression, consistent with allelic exclusion of Vβ-encoding loci. ATOs provide a robust tool for studying human T cell differentiation and for the future development of stem-cell-based engineered T cell therapies.

Aim: The research paper presents the characteristic of cytoarchitectonics of the thymus of intact white mature male laboratory rats. Topicality of the study is due to the need to clarify the data on the contribution of each type of thymus cells in the formation of its structure. The aim of the research was to determine the specifics of localization and ultramicroscopic structure of thymus cells in male mature Wistar laboratory rats. Material and Methods: The study was conducted using histological and ultramicroscopic methods on 10 mature male laboratory rats, weighing 130-150 g. Semi-thin (0.5-1 μm) and ultrathin (0.05-0.2 μm) sections were made on a microtome UMTP-4 (Ukraine), which were stained with 1% methylene blue solution with the addition of 1% sodium tetraborate solution. Histological analysis and photographic recording were performed using Olympus light microscope (Japan) and DSM 510 camcorder with magnification in 1000 times. Results: With a detailed study of the semi-thin and ultrathin sections in the thymus lobules the specifics of localization and ultramicroscopic structure of thymus cells were clearly identified. The features of localization and ultramicroscopic structure of epithelial, mesenchymal, vascular and hematopoietic thymus cells were determined from the point of view of their functional loads and interactions. Conclusion: The described structural peculiarities of the components of the thymus and their relative location in different zones reflect significant organ polymorphism, which must be taken into account in order to achieve the required level of objectivity in the result evaluation of simulated biomedical experiments.

Humanity has an ancient history of consuming medicinal plants for prophylaxis. Within hours, and even months, embryonic cells undergo several processes to form an organism. This study aimed to prove the positive or negative effects of using rosemary and thyme extract on the thymus gland and level of IL-10, IgM, and IgG in serum of chick embryos. The immunological effect was measured by histological and immunological studies. A total of 160 fertilized eggs were randomly distributed into 8 groups; on the 0 and 8th day of incubation, all treated groups received a dose of 0.1 mL/egg. On the 14th and 20th days of incubation, the embryos were sacrificed and the samples were collected (serum and thymus gland). The data were analyzed using ANOVA. Simple damage in thymic tissue with a low cell density in the embryos was treated with high concentrations of rosemary and thyme extracts, as well as in the mixed group. A significant decrease in IgM levels in the group treated by a high concentration of thyme. A decrease in IgG levels was found in the group treated with a high concentration of rosemary and in the mixed group, while the group treated with a high concentration of thyme and the mixed group showed decreases on the 14th day. A significant decrease in IL-10 levels was found on the 14th day, followed by an increase on the 20th day. Despite the benefits of rosemary and thyme, inflammation signs appeared on embryos treated with these herbs.

Background: Chest MRI is a useful diagnostic modality for the evaluation of anterior mediastinal lesions but the outcomes of anterior mediastinal cystic lesions diagnosed on chest MRI are unclear. Methods: In this multicenter retrospective study, patients who underwent contrast-enhanced chest MRI in two tertiary centers to assess anterior mediastinal cystic lesions were included after excluding overt solid tumors and thymic hyperplasia. Anterior mediastinal cystic lesions were classified into two categories: probable (simple) cyst or indeterminate lesion (complex cyst). Size and imaging features of lesions during follow-up were evaluated and clinical outcomes were assessed. Results: A total of 204 patients (mean age, 59 ± 11 years; M:F = 111:93) were studied; 186 (91.2%) were classified as probable cysts and 18 (8.8%) as indeterminate lesions on MRI. Among patients with probable cysts and more than 2 years of follow-up, lesion size was unchanged in 39.6% (36/91), decreased in 16.5% (15/91), and fluctuated in 8.8% (8/91). All patients who underwent surgery were confirmed cysts. None developed mural nodules or irregular wall thickening, suspicious for malignancy during follow-up. In patients with indeterminate lesions, 16.7% (3/18) had pathologically confirmed thymoma and 44.4% (8/18) had proven cysts. Follow-up numbers and intervals after MRI in patients with probable cysts were variable among physicians and institutions in clinical practice (p < 0.05) but more than half were followed for up to 2 years in two centers. Conclusion: Diagnosing anterior mediastinal cysts using MRI is reliable. MRI-based management of anterior mediastinal lesions may reduce the number of unnecessary follow-ups and surgeries. [ABSTRACT FROM AUTHOR]

Objective: To investigate the changes of fetal thymus transverse diameter, anterior and posterior diameter, area and circumference with gestational age (GA), and to establish the Z score model of normal fetal thymus from 20 to 38 weeks. Methods: From September 2020 to May 2021, 612 single pregnant women who underwent routine prenatal examinations in the Third Affiliated Hospital of Henan University of Traditional Chinese Medicine were randomly selected. The transverse diameter, anterior and posterior diameter, area and circumference of the fetal thymus were measured. According to the correlation coefficients between the measured values and GA, biparietal diameter (BPD) and femur length (FL), the optimal indexes for evaluating fetal thymus size were selected. The optimal prediction regression equation and prediction standard deviation (SD) regression equation of fetal thymus were established based on GA, BPD and FL, and the Z -score model was constructed according to the formula Z value =(actual measured thymus value-predicted thymus value)/predicted SD. Results: The two-dimensional measurements of fetal thymus increased with the increase of GA, which was significantly positively correlated with GA (P＜0.001). The correlation between thymus diameter and GA was the highest (r=0.873, P＜0.001). The best fitting equations of fetal thymus diameter with GA, BPD and FL were linear. The predicted regression equation and the predicted standard deviation regression equation of fetal thymus diameter were established successfully, and the Z-values calculated by Shapiro-Wilk test satisfied normal distribution (P＞0.05). Conclusions: Thymus transverse diameter is the best two-dimensional index to evaluate normal fetal thymus size, and the Z-score model of fetal thymus transverse diameter provides a basis for prenatal evaluation of fetal thymus development and early detection of diseases related to abnormal thymus development. [ABSTRACT FROM AUTHOR]

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This study aimed to evaluate how genistein affected the weight and histological structure of the thymus gland in adult and postnatal (P22) female albino mice. Fifteen adult female albino mice and fifteen postnatal (P22) female albino mice were used and divided between two experiments. The animals were divided into three groups (n=5) in each experiment: Group (I), the control group, Group (II), and Group (III), which received 10mg and 50mg genistein/ kg B. W. respectively. In comparison to the control, treatment with 50mg genistein resulted in a significant increase in the weight of the thymus gland in both adult and postnatal mice. When compared to control, treatment with 10mg genistein resulted in a significant increase in this weight in adult females and a significant decrease in the weight of this gland in postnatal mice. Both genistein concentrations had a negative impact on the gland’s histological features. The formation of a "Starry sky" in cortical and medullary regions, an increase in the thickness of regions due to an increase or decrease in the number of T cells depending on genistein concentration, as well as histiocyte hyperplasia and blood vessel congestion, are among these consequences. In conclusion, because genistein affects thymic tissue negatively, it has the potential to create thymic and immunological diseases. [ABSTRACT FROM AUTHOR]

The humanized bone marrow-liver-thymus (BLT) mouse model harbors a nearly complete human immune system, therefore providing a powerful tool to study human immunology and immunotherapy. However, its application is greatly limited by the restricted supply of human CD34+ hematopoietic stem cells and fetal thymus tissues that are needed to generate these mice. The restriction is especially significant for the study of human immune systems with special genetic traits, such as certain human leukocyte antigen (HLA) haplotypes or monogene deficiencies. To circumvent this critical limitation, we have developed a method to quickly propagate established BLT mice. Through secondary transfer of bone marrow cells and human thymus implants from BLT mice into NSG (NOD/SCID/IL-2Rγ-/-) recipient mice, we were able to expand one primary BLT mouse into a colony of 4-5 proBLT (propagated BLT) mice in 6-8 weeks. These proBLT mice reconstituted human immune cells, including T cells, at levels comparable to those of their primary BLT donor mouse. They also faithfully inherited the human immune cell genetic traits from their donor BLT mouse, such as the HLA-A2 haplotype that is of special interest for studying HLA-A2-restricted human T cell immunotherapies. Moreover, an EGFP reporter gene engineered into the human immune system was stably passed from BLT to proBLT mice, making proBLT mice suitable for studying human immune cell gene therapy. This method provides an opportunity to overcome a critical hurdle to utilizing the BLT humanized mouse model and enables its more widespread use as a valuable preclinical research tool.

The generation of distinct hematopoietic cell types, including tissue-resident immune cells, distinguishes fetal from adult hematopoiesis. However, the mechanisms underlying differential cell production to generate a layered immune system during hematopoietic development are unclear. Using an irreversible lineage-tracing model, we identify a definitive hematopoietic stem cell (HSC) that supports long-term multilineage reconstitution upon transplantation into adult recipients but does not persist into adulthood in situ. These HSCs are fully multipotent, yet they display both higher lymphoid cell production and greater capacity to generate innate-like B and T lymphocytes as compared to coexisting fetal HSCs and adult HSCs. Thus, these developmentally restricted HSCs (drHSCs) define the origin and generation of early lymphoid cells that play essential roles in establishing self-recognition and tolerance, with important implications for understanding autoimmune disease, allergy, and rejection of transplanted organs.

T cell egress from the thymus is essential for adaptive immunity and involves chemotaxis along a sphingosine-1-phosphate (S1P) gradient. Pericytes at the corticomedullary junction produce the S1P egress signal, whereas thymic parenchymal S1P levels are kept low through S1P lyase (SPL)-mediated metabolism. Although SPL is robustly expressed in thymic epithelial cells (TECs), in this study, we show that deleting SPL in CD11c+ dendritic cells (DCs), rather than TECs or other stromal cells, disrupts the S1P gradient, preventing egress. Adoptive transfer of peripheral wild-type DCs rescued the egress phenotype of DC-specific SPL knockout mice. These studies identify DCs as metabolic gatekeepers of thymic egress. Combined with their role as mediators of central tolerance, DCs are thus poised to provide homeostatic regulation of thymic export.

Using multiple murine foster-nursing protocols, thereby eliminating placental transfer and allowing a distinction between dam- and pup-derived cells, we show that foster nursing by an immunized dam results in development of CD8(+) T cells in nonimmunized foster pups that are specific for Ags against which the foster dam was immunized (Mycobacterium tuberculosis or Candida albicans). We have dubbed this process "maternal educational immunity" to distinguish it from passive cellular immunity. Of the variety of maternal immune cells present in milk, only T cells were detected in pup tissues. Maternal T cells, a substantial percentage of which were CD4(+)MHC class II(+), accumulated in the pup thymus and spleen during the nursing period. Further analysis of maternal cells in the pup thymus showed that a proportion was positive for maternal immunogen-specific MHC class II tetramers. To determine the outcome of Ag presentation in the thymus, the maternal or foster pup origin of immunogen-responding CD8(+) cells in foster pup spleens was assessed. Whereas ∼10% were maternally derived in the first few weeks after weaning, all immunogen-responding CD8(+) T cells were pup derived by 12 wk of age. Pup-derived immunogen-responsive CD8(+) cells persisted until at least 1 y of age. Passive cellular immunity is well accepted and has been demonstrated in the human population. In this study, we show an arguably more important role for transferred immune cells: the direction of offspring T cell development. Harnessing maternal educational immunity through prepregnancy immunization programs has potential for improvement of infant immunity.

BackgroundAging-associated noncommunicable comorbidities are more prevalent among human immunodeficiency virus type 1 (HIV)-infected individuals than among HIV-uninfected individuals. Residual HIV-related chronic immune activation and senescence may increase the risk of developing comorbidities.MethodsImmune phenotyping, thymic output, and telomere length were assessed in 94 HIV-infected individuals who were aged >45 years and receiving antiretroviral therapy (ART; cases) and 95 age-matched uninfected controls.ResultsCases had lower CD4(+) T-cell counts, higher CD8(+) T-cell counts, and increased levels of immune activation (ie, increased soluble CD14 [sCD14] level and increased percentages of CD38(+)HLA-DR(+) cells among both CD4(+) and CD8(+) T cells), regulatory T cells, and percentage of programmed cell death 1 (PD-1)-expressing cells among CD4(+) T cells. Immune senescence levels (ie, percentages of CD27(-)CD28(-) cells or CD57(+) cells) were comparable between cases and controls. Peripheral blood mononuclear cells from cases had shorter telomeres but increased single-joint T-cell receptor excision circle content and CD31(+) naive CD4(+) T cells. Although cytomegalovirus (CMV) antibody titers were higher in cases, CMV-specific T-cell responses were comparable between cases and controls. T-cell senescence in cases was independently associated with T-cell activation but not with CMV-specific immune responses.ConclusionsDespite long-term receipt of ART, HIV-infected adults had higher levels of immune activation, regulatory T cells, and PD-1-expressing CD4(+) cells and shorter telomeres. The increased soluble CD14 levels and percentage of CD38(+)HLA-DR(+) cells among CD4(+) T cells correlated with shorter telomeres and increased regulatory T-cell levels. This suggests that HIV influences immune function irreversibly, with several pathways that are persistently abnormal during effective ART. Therapies aimed at improving immune health during ART are needed.

Estrogen receptor α (ERα) signaling leads to cellular responses in several tissues and in addition to nuclear ERα-mediated effects, membrane ERα (mERα) signaling may be of importance. To elucidate the significance, in vivo, of mERα signaling in multiple estrogen-responsive tissues, we have used female mice lacking the ability to localize ERα to the membrane due to a point mutation in the palmitoylation site (C451A), so called Nuclear-Only-ER (NOER) mice. Interestingly, the role of mERα signaling for the estrogen response was highly tissue-dependent, with trabecular bone in the axial skeleton being strongly dependent (>80% reduction in estrogen response in NOER mice), cortical and trabecular bone in long bones, as well as uterus and thymus being partly dependent (40-70% reduction in estrogen response in NOER mice) and effects on liver weight and total body fat mass being essentially independent of mERα (

The ability of T cells to respond to a wide array of foreign antigens while avoiding reactivity to self is largely determined by cellular selection of developing T cells in the thymus. While a great deal is known about the cell types and molecules involved in T-cell selection in the thymus, our understanding of the spatial and temporal aspects of this process remain relatively poorly understood. Thymocytes are highly motile within the thymus and travel between specialized microenvironments at different phases of their development while interacting with distinct sets of self-peptides and peptide presenting cells. A knowledge of when, where, and how thymocytes encounter self-peptide MHC ligands at different stages of thymic development is key to understanding T-cell selection. In the past several years, our laboratory has investigated this topic using two-photon time-lapse microscopy to directly visualize thymocyte migration and signaling events, together with a living thymic slice preparation to provide a synchronized experimental model of T-cell selection in situ. Here, we discuss recent advances in our understanding of the temporal and spatial aspects of T-cell selection, highlighting our own work, and placing them in the context of work from other groups.

ObjectivesAIDS is caused by CD4 T-cell depletion. Although combination antiretroviral therapy can restore blood T-cell numbers, the clonal diversity of the reconstituting cells, critical for immunocompetence, is not well defined.MethodsWe performed an extensive analysis of parameters of thymic function in perinatally HIV-1-infected (n = 39) and control (n = 28) participants ranging from 13 to 23 years of age. CD4 T cells including naive (CD27 CD45RA) and recent thymic emigrant (RTE) (CD31/CD45RA) cells, were quantified by flow cytometry. Deep sequencing was used to examine T-cell receptor (TCR) sequence diversity in sorted RTE CD4 T cells.ResultsInfected participants had reduced CD4 T-cell levels with predominant depletion of the memory subset and preservation of naive cells. RTE CD4 T-cell levels were normal in most infected individuals, and enhanced thymopoiesis was indicated by higher proportions of CD4 T cells containing TCR recombination excision circles. Memory CD4 T-cell depletion was highly associated with CD8 T-cell activation in HIV-1-infected persons and plasma interlekin-7 levels were correlated with naive CD4 T cells, suggesting activation-driven loss and compensatory enhancement of thymopoiesis. Deep sequencing of CD4 T-cell receptor sequences in well compensated infected persons demonstrated supranormal diversity, providing additional evidence of enhanced thymic output.ConclusionDespite up to two decades of infection, many individuals have remarkable thymic reserve to compensate for ongoing CD4 T-cell loss, although there is ongoing viral replication and immune activation despite combination antiretroviral therapy. The longer term sustainability of this physiology remains to be determined.

Objective: The objective of this study was to evaluate the association between reduced fetal thymus size and intrauterine growth restriction (IUGR). This study was devised to determine the association between thymus size and any abnormal Doppler indices within the fetal umbilical artery (UA), as well as the middle cerebral artery (MCA). Materials and Methods: Forty-six pregnancies between 20 and 38 weeks of gestation with IUGR and 46 normal pregnancies within similar gestational age (GA) range were included. The transverse diameter of fetal thymus was measured. In the IUGR group, the fetal umbilical artery (UA) and middle cerebral artery (MCA) Doppler flow velocities were recorded. Results: The mean GA of fetuses with IUGR (33.5 weeks) was higher than control group (30.3 weeks). To adjust for the effect of GA, analysis of covariance (ANCOVA) was performed. The adjusted mean thymus diameters were 19.02 mm in IUGR and 21.25 within the control group (mean difference = 2.23 mm; P =.02). The mean (±SD) thymus size in 16 fetuses, with abnormal Doppler findings, was significantly lower than in the group with normal Doppler findings, 17.45 (±2.50) vs 22.02 (±5.39) mm; P <.001. Conclusion: IUGR may be associated with reduced fetal thymus size, especially when coupled with abnormal Doppler findings. The thymus size in a group of IUGR fetuses, with abnormal Doppler findings, was smaller than IUGR fetuses, with normal Doppler findings. [ABSTRACT FROM AUTHOR]

Abstract Background The appearance of the thymus on imaging studies showed great variability. Thymus imaging is a great challenge. This cross-sectional prospective study investigated the diagnostic value of different imaging modalities in the evaluation of normal and diseased thymus. Chest X-ray was done as a primary survey. Chest computed tomography (CT) was done for 82 patients, chest magnetic resonant imaging (MRI) was done for 40 patients, and 18 flurodeoxy glucose positron emission tomography (18 FDG-PET) was done for 2 patients. Ultrasonography (US) of the anterior mediastinum was done for 2 pediatric patients. Histopathological assessment was done for all cases with diseased thymus. Results The study included 158 patients divided into 2 groups: group A, 79 patients with normal thymus for age and group B, 79 patients with thymic lesions detected by one or more of the used modalities. The large-sized thymus was in 79 patients, who were subcategorized to patients with myasthenia gravis (12 patients) and patients with mediastinal masses (67 patients). Imaging findings in normal and diseased thymus gland were compared and lesion analysis by various modalities displayed with histopathological correlation. Conclusion There are different imaging modalities for thymus gland evaluation. CT is beneficial for primary assessment giving the morphology and density, and MRI is the imaging modality of choice in diseased thymus owing to functional assessment of the gland; however, X-ray may be helpful as a primary survey tool before CT and MRI. Chest ultrasound could be a suitable primary assessment tool in pediatrics before MRI because it is an easy bedside test.

This study aimed to evaluate how genistein affected the weight and histological structure of the thymus gland in adult and postnatal (P22) female albino mice. Fifteen adult female albino mice and fifteen postnatal (P22) female albino mice were used and divided between two experiments. The animals were divided into three groups (n=5) in each experiment: Group (I), the control group, Group (II), and Group (III), which received 10mg and 50mg genistein/ kg B. W. respectively. In comparison to the control, treatment with 50mg genistein resulted in a significant increase in the weight of the thymus gland in both adult and postnatal mice. When compared to control, treatment with 10mg genistein resulted in a significant increase in this weight in adult females and a significant decrease in the weight of this gland in postnatal mice. Both genistein concentrations had a negative impact on the gland’s histological features. The formation of a "Starry sky" in cortical and medullary regions, an increase in the thickness of regions due to an increase or decrease in the number of T cells depending on genistein concentration, as well as histiocyte hyperplasia and blood vessel congestion, are among these consequences. In conclusion, because genistein affects thymic tissue negatively, it has the potential to create thymic and immunological diseases.

Background: Preclinical and clinical studies suggest that zinc deficiency and chronic stress contribute to depressive symptoms. Our study explores the intricate relationship between these factors by examining their physiological and biochemical effects across various organs in C57Bl/6J mice., Methods: The mice were divided into four groups: control, chronic restraint stress for 3 weeks, a zinc-restricted diet (<3 mg/kg) for 4 weeks, and a combination of stress and zinc restriction. Mice spleen and thymus weights were measured, and hematoxylin-eosin staining was conducted for liver and intestinal morphometry. Moreover, metallothionein (MT-1, MT-2, and MT-3), zinc transporter (ZnT-1), oxidative stress markers (TBARS, SOD, and GSH-Px), and zinc, iron, and copper concentrations in the liver were evaluated. Immunohistochemical analysis of the jejunum for ZIP1 and ZIP4 was also performed., Conclusions: Our findings reveal that dietary zinc restriction and chronic stress induce structural changes in the intestines and immune organs and impact metallothionein expression, oxidative stress, and liver iron and copper homeostasis.

Studies of repertoires of mouse monoclonal CD4(+) T cells have revealed several mechanisms of self-tolerance; however, which mechanisms operate in normal repertoires is unclear. Here we studied polyclonal CD4(+) T cells specific for green fluorescent protein expressed in various organs, which allowed us to determine the effects of specific expression patterns on the same epitope-specific T cells. Peptides presented uniformly by thymic antigen-presenting cells were tolerated by clonal deletion, whereas peptides excluded from the thymus were ignored. Peptides with limited thymic expression induced partial clonal deletion and impaired effector T cell potential but enhanced regulatory T cell potential. These mechanisms were also active for T cell populations specific for endogenously expressed self antigens. Thus, the immunotolerance of polyclonal CD4(+) T cells was maintained by distinct mechanisms, according to self-peptide expression patterns.