Thymic Function Research Articles

Key Factors for Thymic Function and Development.

The thymus is the organ responsible for T cell development and the formation of the adaptive immunity function. Its multicellular environment consists mainly of the different stromal cells and maturing T lymphocytes. Thymus-specific progenitors of epithelial, mesenchymal, and lymphoid cells with stem cell properties represent only minor populations. The thymic stromal structure predominantly determines the function of the thymus. The stromal components, mostly epithelial and mesenchymal cells, form this specialized area. They support the consistent developmental program of functionally distinct conventional T cell subpopulations. These include the MHC restricted single positive CD4+ CD8- and CD4- CD8+ cells, regulatory T lymphocytes (Foxp3+), innate natural killer T cells (iNKT), and γδT cells. Several physiological causes comprising stress and aging and medical treatments such as thymectomy and chemo/radiotherapy can harm the thymus function. The present review summarizes our knowledge of the development and function of the thymus with a focus on thymic epithelial cells as well as other stromal components and the signaling and transcriptional pathways underlying the thymic cell interaction. These critical thymus components are significant for T cell differentiation and restoring the thymic function after damage to reach the therapeutic benefits.

Differentiation of Pluripotent Stem Cells Into Thymic Epithelial Cells and Generation of Thymic Organoids: Applications for Therapeutic Strategies Against APECED

The thymus is a primary lymphoid organ essential for the induction of central immune tolerance. Maturing T cells undergo several steps of expansion and selection mediated by thymic epithelial cells (TECs). In APECED and other congenital pathologies, a deficiency in genes that regulate TEC development or their ability to select non auto-reactive thymocytes results in a defective immune balance, and consequently in a general autoimmune syndrome. Restoration of thymic function is thus crucial for the emergence of curative treatments. The last decade has seen remarkable progress in both gene editing and pluripotent stem cell differentiation, with the emergence of CRISPR-based gene correction, the trivialization of reprogramming of somatic cells to induced pluripotent stem cells (iPSc) and their subsequent differentiation into multiple cellular fates. The combination of these two approaches has paved the way to the generation of genetically corrected thymic organoids and their use to control thymic genetic pathologies affecting self-tolerance. Here we review the recent advances in differentiation of iPSc into TECs and the ability of the latter to support a proper and efficient maturation of thymocytes into functional and non-autoreactive T cells. A special focus is given on thymus organogenesis and pathway modulation during iPSc differentiation, on the impact of the 2/3D structure on the generated TECs, and on perspectives for therapeutic strategies in APECED based on patient-derived iPSc corrected for AIRE gene mutations.

Immunological differences between heart- and kidney-transplanted children: a cross-sectional study.

Post-transplantation lymphoproliferative disorder is a potentially mortal complication after heart transplantation in children. As the immune system plays a crucial role in the development of lymphoma, we explored the influence of thymus function in relation to immunosuppressive treatment in organ-transplanted children and healthy control subjects. A prospective case-control study was performed at a single centre, in which 36 children who had undergone heart transplantation were compared to two control groups: 34 kidney-transplanted children and 33 healthy age- and sex-matched children. T- and B-lymphocyte subtypes and monocytes were analysed by flow cytometry, and T-cell receptor excision circles were assessed using quantitative polymerase chain reaction. Heart-transplanted children had a lymphocyte profile characterised by reduced or absent thymic function with low numbers of T-cell receptor excision circles and total and naïve T cells, together with immune activation against the allograft. Despite similar immunosuppressive treatment, the kidney-transplanted group showed an activated T-lymphocyte compartment.

Thymus Functionality Needs More Than a Few TECs.

The thymus, a primary lymphoid organ, produces the T cells of the immune system. Originating from the 3rd pharyngeal pouch during embryogenesis, this organ functions throughout life. Yet, thymopoiesis can be transiently or permanently damaged contingent on the types of systemic stresses encountered. The thymus also undergoes a functional decline during aging, resulting in a progressive reduction in naïve T cell output. This atrophy is evidenced by a deteriorating thymic microenvironment, including, but not limited, epithelial-to-mesenchymal transitions, fibrosis and adipogenesis. An exploration of cellular changes in the thymus at various stages of life, including mouse models of in-born errors of immunity and with single cell RNA sequencing, is revealing an expanding number of distinct cell types influencing thymus functions. The thymus microenvironment, established through interactions between immature and mature thymocytes with thymus epithelial cells (TEC), is well known. Less well appreciated are the contributions of neural crest cell-derived mesenchymal cells, endothelial cells, diverse hematopoietic cell populations, adipocytes, and fibroblasts in the thymic microenvironment. In the current review, we will explore the contributions of the many stromal cell types participating in the formation, expansion, and contraction of the thymus under normal and pathophysiological processes. Such information will better inform approaches for restoring thymus functionality, including thymus organoid technologies, beneficial when an individuals’ own tissue is congenitally, clinically, or accidentally rendered non-functional.

Signaling Crosstalks Drive Generation and Regeneration of the Thymus.

Optimal recovery of immune competence after periods of hematopoietic insults or stress is crucial to re-establish patient response to vaccines, pathogens and tumor antigens. This is particularly relevant for patients receiving high doses of chemotherapy or radiotherapy, who experience prolonged periods of lymphopenia, which can be associated with an increased risk of infections, malignant relapse, and adverse clinical outcome. While the thymus represents the primary organ responsible for the generation of a diverse pool of T cells, its function is profoundly impaired by a range of acute insults (including those caused by cytoreductive chemo/radiation therapy, infections and graft-versus-host disease) and by the chronic physiological deterioration associated with aging. Impaired thymic function increases the risk of infections and tumor antigen escape due to a restriction in T-cell receptor diversity and suboptimal immune response. Therapeutic approaches that can promote the renewal of the thymus have the potential to restore immune competence in patients. Previous work has documented the importance of the crosstalk between thymocytes and thymic epithelial cells in establishing correct architecture and function of thymic epithelium. This crosstalk is relevant not only during thymus organogenesis, but also to promote the recovery of its function after injuries. In this review, we will analyze the signals involved in the crosstalk between TECs and hematopoietic cells. We will focus in particular on how signals from T-cells can regulate TEC function and discuss the relevance of these pathways in restoring thymic function and T-cell immunity in experimental models, as well as in the clinical setting.

Low Memory T Cells Blood Counts and High Naïve Regulatory T Cells Percentage at Relapsing Remitting Multiple Sclerosis Diagnosis.

ObjectiveThe aim of this study is to assess the peripheral immune system of newly diagnosed patients with relapsing remitting multiple sclerosis (RRMS) and compare it to healthy controls (HC).MethodsThis cross-sectional study involves 30 treatment-naïve newly diagnosed patients with RRMS and 33 sex- and age-matched HC. Peripheral blood mononuclear cells were analyzed regarding: i) thymic function surrogates [T cell receptor excision circles (TRECs) and recent thymic emigrants (RTEs)]; ii) naïve and memory CD4+ and CD8+ T cells subsets; iii) T helper (Th) phenotype and chemokine receptors expression on CD8+ T cells subsets; iv) regulatory T cell (Tregs) phenotype; and exclude expression of activating/inhibitory receptors by natural killer (NK) and NKT cells. Analyses were controlled for age, sex, and human cytomegalovirus (HCMV) IgG seroprevalence.ResultsNewly diagnosed patients with RRMS and HC have equivalent thymic function as determined by similar numbers of RTEs and levels of sjTRECs, DJβTRECs, and sj/DJβTREC ratio. In the CD8+ T cells compartment, patients with RRMS have a higher naive to memory ratio and lower memory cell counts in blood, specifically of effector memory and TemRA CD8+ T cells. Interestingly, higher numbers and percentages of central memory CD8+ T cells are associated with increasing time from the relapse. Among CD4+ T cells, lower blood counts of effector memory cells are found in patients upon controlling for sex, age, and anti-HCMV IgG seroprevalence. Higher numbers of CD4+ T cells (both naïve and memory) and of Th2 cells are associated with increasing time from the relapse; lower numbers of Th17 cells are associated with higher MS severity scores (MSSS). Patients with RRMS have a higher percentage of naïve Tregs compared with HC, and lower percentages of these cells are associated with higher MSSS. Percentages of immature CD56bright NK cells expressing the inhibitory receptor KLRG1 and of mature CD56dimCD57+ NK cells expressing NKp30 are higher in patients. No major alterations are observed on NKT cells.ConclusionCharacterization of the peripheral immune system of treatment-naïve newly diagnosed patients with RRMS unveiled immune features present at clinical onset including lower memory T cells blood counts, particularly among CD8+ T cells, higher percentage of naïve Tregs and altered percentages of NK cells subsets expressing inhibitory or activating receptors. These findings might set the basis to better understand disease pathogenesis.

Abrogation of Notch Signaling in Embryonic TECs Impacts Postnatal mTEC Homeostasis and Thymic Involution.

Notch signaling is crucial for fate specification and maturation of thymus-seeding progenitors along the T-cell lineage. Recent studies have extended the role of Notch signaling to thymic epithelial cells (TECs), showing that Notch regulates TEC progenitor maintenance and emergence of medullary TECs (mTECs) in fetal thymopoiesis. Based on immunohistochemistry studies of spatiotemporal regulation of Notch activation in the postnatal thymus, we show that in vivo Notch activation is not confined to fetal TECs. Rather, Notch signaling, likely mediated through the Notch1 receptor, is induced in postnatal cortical and medullary TECs, and increases significantly with age in the latter, in both humans and mice, suggesting a conserved role for Notch signaling in TEC homeostasis during thymus aging. To investigate the functional impact of Notch activation in postnatal TEC biology, we used a mouse model in which RPBJκ, the transcriptional effector of canonical Notch signaling, is deleted in epithelial cells, including TECs, under the control of the transcription factor Foxn1. Immunohistochemistry and flow cytometry analyses revealed no significant differences in TEC composition in mutant (RPBJκ-KOTEC) and wild-type (WT) littermate mice at early postnatal ages. However, a significant reduction of the medullary region was observed in mutant compared to WT older thymi, which was accompanied by an accelerated decrease of postnatal mTEC numbers. Also, we found that organization and integrity of the postnatal thymic medulla critically depends on activation of the canonical Notch signaling pathway, as abrogation of Notch signaling in TECs led to the disruption of the medullary thymic microenvironment and to an accelerated thymus atrophy. These features paralleled a significant increase in the proportion of intrathymic non-T lineage cells, mostly B cells, and a slight decrease of DP thymocyte numbers compatible with a compromised thymic function in mutant mice. Therefore, impaired Notch signaling induced in embryonic development impacts postnatal TECs and leads to an accelerated mTEC degeneration and a premature thymus involution. Collectively, our data have uncovered a new role for Notch1 signaling in the control of adult mTEC homeostasis, and point toward Notch signaling manipulation as a novel strategy for thymus regeneration and functional recovery from immunosenescence.

Structural and Functional Thymic Biomarkers Are Involved in the Pathogenesis of Thymic Epithelial Tumors: An Overview

The normal human thymus originates from the third branchial cleft as two paired anlages that descend into the thorax and fuse on the midline of the anterior–superior mediastinum. Alongside the epithelial and lymphoid components, different types of lymphoid accessory cells, stromal mesenchymal and endothelial cells migrate to, or develop in, the thymus. After reaching maximum development during early postnatal life, the human thymus decreases in size and lymphocyte output drops with age. However, thymic immunological functions persist, although they deteriorate progressively. Several major techniques were fundamental to increasing the knowledge of thymic development and function during embryogenesis, postnatal and adult life; these include immunohistochemistry, immunofluorescence, flow cytometry, in vitro colony assays, transplantation in mice models, fetal organ cultures (FTOC), re-aggregated thymic organ cultures (RTOC), and whole-organ thymic scaffolds. The thymic morphological and functional characterization, first performed in the mouse, was then extended to humans. The purpose of this overview is to provide a report on selected structural and functional biomarkers of thymic epithelial cells (TEC) involved in thymus development and lymphoid cell maturation, and on the historical aspects of their characterization, with particular attention being paid to biomarkers also involved in Thymic Epithelial Tumor (TET) pathogenesis. Moreover, a short overview of targeted therapies in TET, based on currently available experimental and clinical data and on potential future advances will be proposed.

Identification of fibroblast progenitors in the developing mouse thymus.

ABSTRACTThe thymus stroma constitutes a fundamental microenvironment for T-cell generation. Despite the chief contribution of thymic epithelial cells, recent studies emphasize the regulatory role of mesenchymal cells in thymic function. Mesenchymal progenitors are suggested to exist in the postnatal thymus; nonetheless, an understanding of their nature and the mechanism controlling their homeostasis in vivo remains elusive. We resolved two new thymic fibroblast subsets with distinct developmental features. Whereas CD140αβ+GP38+SCA-1− cells prevailed in the embryonic thymus and declined thereafter, CD140αβ+GP38+SCA-1+ cells emerged in the late embryonic period and predominated in postnatal life. The fibroblastic-associated transcriptional programme was upregulated in CD140αβ+GP38+SCA-1+ cells, suggesting that they represent a mature subset. Lineage analysis showed that CD140αβ+GP38+SCA-1+ maintained their phenotype in thymic organoids. Strikingly, CD140αβ+GP38+SCA-1− generated CD140αβ+GP38+SCA-1+, inferring that this subset harboured progenitor cell activity. Moreover, the abundance of CD140αβ+GP38+SCA-1+ fibroblasts was gradually reduced in Rag2−/− and Rag2−/−Il2rg−/− thymi, indicating that fibroblast maturation depends on thymic crosstalk. Our findings identify CD140αβ+GP38+SCA-1− as a source of fibroblast progenitors and define SCA-1 as a marker for developmental stages of thymic fibroblast differentiation.

Characterization of thymic epithelial cell and thymocyte function and development in patients with thymic defects using scRNAseq profiling

Abstract The interaction between thymocytes and thymic epithelial cells (TEC) in the thymus is critical for the correct function and maturation of both cell populations and for the development of a diverse repertoire of non-self-reactive T-cell lymphocytes. Limited information is available on lympho-stromal crosstalk in the thymus of patients carrying thymic defects. We have previously shown that thymic tissues from DiGeorge syndrome (DGS) and Down syndrome (DS) patients have alterations in architecture and TEC composition, leading to altered T-cell development. Based on these results, we are performing single cell RNAseq (scRNAseq) to explore the transcriptional landscape of both stromal and hematopoietic components in the human thymus. Thanks to a collaboration with the pediatric cardiothoracic surgery center at the Children’s National Medical Center in Washington D.C., we have access to discarded thymic samples obtained from pediatric patients with partial DGS and DS, and from patients without immune defects. Preliminary results of scRNAseq analysis comparing tissues from normal donors and DS patients revealed a different distribution of cell subsets in both hematopoietic and stromal compartments, with several pathways differentially regulated, such as stress and metabolic processes. Additionally, we established a collaboration with the Thoracic and Gastrointestinal Malignancies Branch at the National Cancer Institute and are evaluating samples obtained from resected thymic epithelial tumors. Integration of data obtained from normal and diseased thymic tissue will provide novel insights into the function and development of the human thymus that could be helpful in the clinical management of patients with thymic defects. This research was supported by the Intramural Research Programs of the NIAID and the NCI (Center for Cancer Research), NIH

22q11.2 Deletion Syndrome Causes a Thymus Hypoplasia Corrected by Mesenchymal Cell Replacement

Abstract Thymus hypoplasia occurs in several clinical conditions including 22q11.2 deletion syndrome (22q11.2DS). 22q11.2DS is the most common human microdeletion disorder, affecting 1/4000. Thymuses from 60–70% 22q11.2DS patients are small and produce fewer T cells than normal. For individuals with a severe hypoplasia, an allogenic thymus tissue graft is needed to restore thymopoiesis. To determine the molecular mechanisms contributing to a small thymus in 22q11.2DS, we compared the development of the thymus in embryos from various 22q11.DS mouse models, normal controls and Foxn1 mutant mice. Reaggregate fetal thymic organ culture assays reveal that replacing mesenchymal cells from 22q11.2del hypoplastic lobes with normal ones restores tissue expansion and thymopoiesis. Thymic epithelial cells used as substitutes cannot. This is distinct from the Foxn1 mutant mice, wherein defective thymic epithelial cell functions lead to thymus hypoplasia/aplasia. Single cell RNA sequencing of normal and hypoplastic thymus lobes revealed differential expression of transcripts that primarily impacted 5 distinct mesenchymal cell subsets in 22q11.2DS. These transcripts are involved in cell-cell interactions, collagen deposition and growth. Elevated levels of collagen are present in the hypoplastic thymus tissues, suggesting a structural restriction. Mesenchymal and epithelial cell differentiation/expansion assays reveal a selective reduction in mesenchymal tissue expansion due to 22q11.2DS Supported by grants from the National Institutes of Health (R01AI114523, R21AI144140) and the Jeffrey Modell Foundation (MdlM, CAW)

Role of paracrine mTOR signaling in regulating thymus size and function.

Abstract The thymus is the primary site of T cell generation, and the unique thymic stromal microenvironment directs T cell differentiation, self-tolerance and self-restriction. However, the size of the thymus declines precipitously relatively early in life, resulting in declining production of naïve T cells. Homeostatic mechanisms drive a shift toward an oligoclonal T cell memory, leaving the elderly less responsive to vaccines and new infections, especially viral infections. Preventing or reversing age-associated thymic atrophy therefore holds potential for extending the healthspan. Mechanisms governing thymic atrophy have been difficult to identify because the primary targets of atrophy, cortical thymic stromal cells, are rare and difficult to isolate. Using an informatic approach to characterize the transcriptional response of thymic stromal cells during age-related atrophy or experimental regeneration, we previously showed that cortical thymic epithelial cells (cTECs) display a unique morphology characterized by extensive looping projections. Atrophy is associated with contraction of these projections, which are renewed during induced regeneration. Further informatic analysis suggested that paracrine mTOR signaling in cTECs promoted by ligands expressed in medullary TECs (mTECs) may be required to maintain the cellular architecture of the cortical stroma and preserve thymus size. To test these hypotheses, we generated two new tissue-specific transgenic mouse lines overexpressing mTOR-activating ligands (IGF1 and FGF21) in most mTECs. Ongoing experiments aim to characterize the impact of increased paracrine mTOR signaling on age-associated thymic dysfunction. This work was supported by N.I.H. R21AI154109. Supported by grant from NIH (R21 AI154109)

The role of autophagy in thymic stromal cell maintenance with age

Abstract T lymphocytes develop in the thymus, where mutually inductive signaling between lymphoid progenitors and thymic stromal cells (TSCs) directs the progenitors along a well-characterized program of differentiation. However, the biology of the TSCs comprising the lymphopoietic thymic microenvironment remains relatively under-characterized because stromal cells are rare and difficult to isolate. TSCs exhibit high basal levels of autophagy at the steady state, which is critical for self-antigen presentation and T cell selection. The mechanisms governing high basal autophagy in TSCs are unknown, however autophagy is induced by many stressors, including high H202 levels. Using a deconvolution technique to study gene expression essentially in situ, we previously identified a deficiency in the H202 quenching enzyme catalase (CAT) in TSCs, and found that CAT deficiency results in high H202 levels in this population, eventually leading to thymic atrophy. Our current studies address the possibility that, in addition to a role in self-antigen presentation, autophagy may also mitigate thymic atrophy through its role in removing organelle damaged by H202. Our preliminary studies suggest that increased basal autophagy in Beclin 1 knock-in (Becn1F121A/F121A) mice promotes thymus function during aging. Supported by N.I.H. grant R01AI121367

Anti-RANKL Inhibits Thymic Function and Causes DRONJ in Mice.

Background Denosumab, a human monoclonal antibody against receptor activator of nuclear factor-kappa B ligand (RANKL), is a novel bone antiresorptive agent used in patients with osteoporosis or metastatic bone cancer. Denosumab-related osteonecrosis of the jaw (DRONJ) has been recently reported in patients using denosumab. However, the mechanisms of DRONJ are not fully understood. Appropriate pathogenic mechanisms of DRONJ have yet to be established. Therefore, we investigated the pathogenesis of DRONJ in mice. Methods Anti-mouse RANKL monoclonal antibody and melphalan were performed to create a mouse model of DRONJ-like lesions in female C57BL/6J mice. We examined the development of DRONJ-like lesions and immune function. Results We showed that administration of anti-mouse RANKL monoclonal antibody and melphalan caused DRONJ-like lesions that recapitulated major clinical manifestations of the human disease, including the characteristic features of an open alveolar socket and exposed necrotic bone. In the analysis using a mouse model of DRONJ-like lesion, it was revealed that anti-mouse RANKL monoclonal antibody and melphalan suppress autoimmune regulator (AIRE) expression in the thymus and imbalanced T cell populations. Conclusion This study suggests evidence of an immunity-based mechanism of DRONJ-like disease. This work may contribute to a better understanding of the pathogenesis of human DRONJ.

Activation of the zinc-sensing receptor GPR39 promotes T-cell reconstitution after hematopoietic cell transplant in mice

AbstractProlonged lymphopenia represents a major clinical problem after cytoreductive therapies such as chemotherapy and the conditioning required for hematopoietic stem cell transplant (HCT), contributing to the risk of infections and malignant relapse. Restoration of T-cell immunity depends on tissue regeneration in the thymus, the primary site of T-cell development, although the capacity of the thymus to repair itself diminishes over its lifespan. However, although boosting thymic function and T-cell reconstitution is of considerable clinical importance, there are currently no approved therapies for treating lymphopenia. Here we found that zinc (Zn) is critically important for both normal T-cell development and repair after acute damage. Accumulated Zn in thymocytes during development was released into the extracellular milieu after HCT conditioning, where it triggered regeneration by stimulating endothelial cell production of BMP4 via the cell surface receptor GPR39. Dietary supplementation of Zn was sufficient to promote thymic function in a mouse model of allogeneic HCT, including enhancing the number of recent thymic emigrants in circulation although direct targeting of GPR39 with a small molecule agonist enhanced thymic function without the need for prior Zn accumulation in thymocytes. Together, these findings not only define an important pathway underlying tissue regeneration but also offer an innovative preclinical approach to treat lymphopenia in HCT recipients.

Eosinophils are an essential element of a type 2 immune axis that controls thymus regeneration.

Therapeutic interventions used for cancer treatment provoke thymus damage and limit the recovery of protective immunity. Here, we show eosinophils are an essential part of an intrathymic type 2 immune network that enables thymus recovery following ablative therapy. Within hours of damage, the thymus undergoes CCR3-dependent colonisation by peripheral eosinophils, which re-establishes the epithelial microenvironments that control thymopoiesis. Eosinophil regulation of thymus regeneration occurs via the concerted action of NKT-cells that trigger CCL11 production via IL4 receptor signalling in thymic stroma, and ILC2 that represent an intrathymic source of IL5, a cytokine that therapeutically boosts thymus regeneration following damage. Collectively, our findings identify an intrathymic network composed of multiple innate immune cells that restores thymus function during re-establishment of the adaptive immune system.

Dynamics of recent thymic emigrants in pediatric recipients of allogeneic hematopoetic stem cell transplantation.

After allogeneic hematopoietic stem cell transplantation (allo-HSCT), the recurrence of recent thymic emigrants (RTE) and self-tolerant T cells indicate normalized thymic function. From 2008 to 2019, we retrospectively analyzed the RTE-reconstitution rate and the minimal time to reach normal age-specific first percentiles for CD31+CD45RA+CD4+T cells in 199 pediatric patients after allo-HSCT for various malignant and non-malignant diseases. The impact of clinically significant graft-versus-host disease (GvHD), age at transplantation, underlying disease and cumulative area under the curve of busulfan on RTE-reemergence was assessed in multivariable longitudinal analysis. RTE-reconstitution (coefficient -0.24, 95% CI -0.33 to-0.14, p < 0.001) was slowed down by GvHD and the time to reach P1 was significantly longer (Event Time Ratio 1.49, 95% CI 1.25 to 1.78, p < 0.001). Older age at transplantation was also associated with a slower RTE-reconstitution (coefficient -0.028, 95% CI -0.04 to -0.02, p < 0.001) and time to reach P1 was significantly longer (Event Time Ratio 1.03, 95% CI 1.02 to 1.05, p < 0.001). RTE-reconstitution velocity was not influenced by underlying disease or cumulative busulfan exposure. In summary, duration until thymic reactivation was independent of both conditioning intensity and underlying disease and was negatively influenced by older age and GvHD.

Redox regulation of age-associated defects in generation and maintenance of Tcell self-tolerance and immunity to foreign antigens.

SUMMARYThymic atrophy reduces naive T cell production and contributes to increased susceptibility to viral infection with age. Expression of tissue-restricted antigen (TRA) genes also declines with age and has been thought to increase autoimmune disease susceptibility. We find that diminished expression of a model TRA gene in aged thymic stromal cells correlates with impaired clonal deletion of cognate T cells recognizing an autoantigen involved in atherosclerosis. Clonal deletion in the polyclonal thymocyte population is also perturbed. Distinct age-associated defects in the generation of antigen-specific T cells include a conspicuous decline in generation of T cells recognizing an immunodominant influenza epitope. Increased catalase activity delays thymic atrophy, and here, we show that it mitigates declining production of influenza-specific T cells and their frequency in lung after infection, but does not reverse declines in TRA expression or efficient negative selection. These results reveal important considerations for strategies to restore thymic function.

Probiotic Consumption Boosts Thymus in Obesity and Senescence Mouse Models.

The ability of the immune system to respond to different pathogens throughout life requires the constant production and selection of T cells in the thymus. This immune organ is very sensitive to age, infectious processes and nutrition disorders (obesity and malnutrition). Several studies have shown that the incorporation of some probiotic bacteria or probiotic fermented milk in the diet has beneficial effects, not only at the intestinal level but also on distant mucosal tissues, improving the architecture of the thymus in a malnutrition model. The aim of the present study was to determine whether supplementation with the probiotic strain Lactobacillus casei CRL 431 and/or its cell wall could improve body weight, intestinal microbiota and thymus structure and function in both obese and aging mice. We evaluated probiotic administration to BALB/c mice in 2 experimental mouse models: obesity and senescence, including mice of different ages (21, 28, 45, 90 and 180 days). Changes in thymus size and histology were recorded. T-lymphocyte population and cytokine production were also determined. The consumption of probiotics improved the cortical/medullary ratio, the production and regulation of cytokines and the recovery of mature T-lymphocyte populations of the thymus in obese and old mice. Probiotic incorporation into the diet could not only modulate the immune system but also lead to thymus function recovery, thus improving quality of life.

P63 targeted deletion under the FOXN1 promoter disrupts pre-and post-natal thymus development, function and maintenance as well as induces severe hair loss.

Progressive immune deficiency of aging is characterized by severe thymic atrophy, contracted T cell repertoire, and poor immune function. p63 is critical for the proliferative potential of embryonic and adult stem cells, as well as thymic epithelial cells (TECs). Because p63 null mice experience rapid post-natal lethality due to epidermal and limb morphogenesis defects, studies to define a role for p63 expression in TEC biology focused on embryonic thymus development and in vitro experiments. Since post-natal thymic stromal development and function differs from that of the embryo, we assessed the impact of lineage-restricted p63 loss on pre- and post-natal murine TEC function by generating mice with a loss of p63 function targeted to TEC, termed p63TECko mice. In adult p63TECko mice, severe thymic hypoplasia was observed with a lack in a discernable segregation into medullary and cortical compartments and peripheral T cell lymphopenia. This profound thymic defect was seen in both neonatal as well as embryonic p63TECko mice. In addition to TECs, p63 also plays in important role in the development of stratified epithelium of the skin; lack of p63 results in defects in skin epidermal stratification and differentiation. Interestingly, all adult p63TECko mice lacked hair follicles despite having normal p63 expression in the skin. Together our results show a critical role of TEC p63 in thymic development and maintenance and show that p63 expression is critical for hair follicle formation.