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1.
Adv Exp Med Biol ; 1444: 33-49, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38467971

RESUMO

Since its discovery, Aire has been the topic of numerous studies in its role as a transcriptional regulator in the thymus where it promotes the "promiscuous" expression of a large repertoire of tissue-restricted antigens (TRAs) that are normally expressed only in the immune periphery. This process occurs in specialized medullary thymic epithelial cells (mTECs) and mediates the elimination of self-reactive T cells or promotes their conversion to the Foxp3+ regulatory T cell lineage, both of which are required for the prevention of autoimmunity. In recent years, there has been increasing interest in the role of extrathymic Aire expression in peripheral organs. The focus has primarily been on the identification of the cellular source(s) and mechanism(s) by which extrathymic AIRE affects tolerance-related or other physiological processes. A cadre of OMICs tools including single cell RNA sequencing and novel transgenic models to trace Aire expression to perform lineage tracing experiments have shed light on a phenomenon that is more complex than previously thought. In this chapter, we provide a deeper analysis of how extrathymic Aire research has developed and progressed, how cellular sources were identified, and how the function of AIRE was determined. Current data suggests that extrathymic AIRE fulfills a function that differs from what has been observed in the thymus and strongly argues that its main purpose is to regulate transcriptional programs in a cell content-dependent manner. Surprisingly, there is data that also suggests a non-transcriptional role of extrathymic AIRE in the cytoplasm. We have arrived at a potential turning point that will take the field from the classical understanding of AIRE as a transcription factor in control of TRA expression to its role in immunological and non-immunological processes in the periphery.


Assuntos
Regulação da Expressão Gênica , Fatores de Transcrição , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Timo , Autoimunidade , Antígenos , Células Epiteliais/metabolismo
2.
Adv Exp Med Biol ; 1444: 19-32, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38467970

RESUMO

One of the difficulties in studying the pathogenesis of autoimmune diseases is that the disease is multifactorial involving sex, age, MHC, environment, and some genetic factors. Because deficiency of Aire, a transcriptional regulator, is an autoimmune disease caused by a single gene abnormality, Aire is an ideal research target for approaching the enigma of autoimmunity, e.g., the mechanisms underlying Aire deficiency can be studied using genetically modified animals. Nevertheless, the exact mechanisms of the breakdown of self-tolerance due to Aire's dysfunction have not yet been fully clarified. This is due, at least in part, to the lack of information on the exact target genes controlled by Aire. State-of-the-art research infrastructures such as single-cell analysis are now in place to elucidate the essential function of Aire. The knowledge gained through the study of Aire-mediated tolerance should help our understanding of the pathogenesis of autoimmune disease in general.


Assuntos
Doenças Autoimunes , Poliendocrinopatias Autoimunes , Animais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Autoimunidade/genética , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/metabolismo , Aprendizagem , Timo
3.
Front Immunol ; 15: 1321309, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38469297

RESUMO

Background: The thymus plays a central role in shaping human immune function. A mechanistic, quantitative description of immune cell dynamics and thymic output under homeostatic conditions and various patho-physiological scenarios are of particular interest in drug development applications, e.g., in the identification of potential therapeutic targets and selection of lead drug candidates against infectious diseases. Methods: We here developed an integrative mathematical model of thymocyte dynamics in human. It incorporates mechanistic features of thymocyte homeostasis as well as spatial constraints of the thymus and considerations of age-dependent involution. All model parameter estimates were obtained based on published physiological data of thymocyte dynamics and thymus properties in mouse and human. We performed model sensitivity analyses to reveal potential therapeutic targets through an identification of processes critically affecting thymic function; we further explored differences in thymic function across healthy subjects, multiple sclerosis patients, and patients on fingolimod treatment. Results: We found thymic function to be most impacted by the egress, proliferation, differentiation and death rates of those thymocytes which are most differentiated. Model predictions also showed that the clinically observed decrease in relapse risk with age, in multiple sclerosis patients who would have discontinued fingolimod therapy, can be explained mechanistically by decreased thymic output with age. Moreover, we quantified the effects of fingolimod treatment duration on thymic output. Conclusions: In summary, the proposed model accurately describes, in mechanistic terms, thymic output as a function of age. It may be further used to perform predictive simulations of clinically relevant scenarios which combine specific patho-physiological conditions and pharmacological interventions of interest.


Assuntos
Esclerose Múltipla , Timócitos , Humanos , Camundongos , Animais , Timócitos/metabolismo , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Cloridrato de Fingolimode/metabolismo , Timo , Diferenciação Celular , Esclerose Múltipla/metabolismo
4.
Nat Commun ; 15(1): 2194, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38467629

RESUMO

The regulation of thymocyte development by RNA-binding proteins (RBPs) is largely unexplored. We identify 642 RBPs in the thymus and focus on Arpp21, which shows selective and dynamic expression in early thymocytes. Arpp21 is downregulated in response to T cell receptor (TCR) and Ca2+ signals. Downregulation requires Stim1/Stim2 and CaMK4 expression and involves Arpp21 protein phosphorylation, polyubiquitination and proteasomal degradation. Arpp21 directly binds RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. Analysis of the Arpp21-bound transcriptome reveals strong interactions with the Rag1 3'-UTR. Arpp21-deficient thymocytes show reduced Rag1 expression, delayed TCR rearrangement and a less diverse TCR repertoire. This phenotype is recapitulated in Rag1 3'-UTR mutant mice harboring a deletion of the Arpp21 response region. These findings show how thymocyte-specific Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until signals from the TCR terminate Arpp21 and Rag1 activities.


Assuntos
Receptores de Antígenos de Linfócitos T , Timócitos , Animais , Camundongos , Diferenciação Celular/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Timócitos/metabolismo , Timo/metabolismo
5.
J Robot Surg ; 18(1): 112, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38441746

RESUMO

The conventional supine position for robotic thymectomy may present challenges in accessing the lower thymic horns, particularly in cases requiring extensive resection of mediastinal fat. To address this issue, the authors advocate for a lateral patient position during the procedure, emphasizing optimized access to the thymic horns and improved procedural efficacy. The lateral approach involves specific trocar placements and port arrangements to minimize conflicts between instruments. This report proposes an innovative approach to robotic thymectomy for patients diagnosed with thymoma or thymic hyperplasia associated with myasthenia gravis.


Assuntos
Procedimentos Cirúrgicos Robóticos , Neoplasias do Timo , Animais , Humanos , Timectomia , Procedimentos Cirúrgicos Robóticos/métodos , Timo , Postura , Neoplasias do Timo/cirurgia
6.
Sci Adv ; 10(11): eadj2802, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38489359

RESUMO

Development of T cells is controlled by the signal strength of the TCR. The scaffold protein kinase D-interacting substrate of 220 kilodalton (Kidins220) binds to the TCR; however, its role in T cell development was unknown. Here, we show that T cell-specific Kidins220 knockout (T-KO) mice have strongly reduced invariant natural killer T (iNKT) cell numbers and modest decreases in conventional T cells. Enhanced apoptosis due to increased TCR signaling in T-KO iNKT thymocytes of developmental stages 2 and 3 shows that Kidins220 down-regulates TCR signaling at these stages. scRNA-seq indicated that the transcription factor Aiolos is down-regulated in Kidins220-deficient iNKT cells. Analysis of an Aiolos KO demonstrated that Aiolos is a downstream effector of Kidins220 during iNKT cell development. In the periphery, T-KO iNKT cells show reduced TCR signaling upon stimulation with α-galactosylceramide, suggesting that Kidins220 promotes TCR signaling in peripheral iNKT cells. Thus, Kidins220 reduces or promotes signaling dependent on the iNKT cell developmental stage.


Assuntos
Fator de Transcrição Ikaros , Proteínas de Membrana , Células T Matadoras Naturais , Timo , Animais , Camundongos , Diferenciação Celular , Regulação da Expressão Gênica , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Proteínas de Membrana/metabolismo , Fator de Transcrição Ikaros/metabolismo , Timo/citologia , Timo/metabolismo
7.
Immunohorizons ; 8(3): 242-253, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38446446

RESUMO

T cell immunity, including CD4+ and CD8+ T cell immunity, is critical to host immune responses to infection. Transcriptomic analyses of both CD4+ and CD8+ T cells of C57BL/6 mice show high expression the gene encoding embigin, Emb, which encodes a transmembrane glycoprotein. Moreover, we found that lung CD4+ Th17 tissue-resident memory T cells of C57BL/6 mice also express high levels of Emb. However, deletion of Emb in αß T cells of C57BL/6 mice revealed that Emb is dispensable for thymic T cell development, generation of lung Th17 tissue-resident memory T cells, tissue-resident memory T cell homing to the lung, experimental autoimmune encephalitis, as well as clearance of pulmonary viral or fungal infection. Thus, based on this study, embigin appears to play a minor role if any in αß T cell development or αß T cell effector functions in C57BL/6 mice.


Assuntos
Linfócitos T CD8-Positivos , Timo , Camundongos , Animais , Camundongos Endogâmicos C57BL , Diferenciação Celular , Células Th17
8.
J Clin Immunol ; 44(3): 79, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38457046

RESUMO

Congenital athymia is a rare T-lymphocytopaenic condition, which requires early corrective treatment with thymus transplantation (TT). Athymic patients are increasingly identified through newborn screening (NBS) for severe combined immunodeficiency (SCID). Lack of relatable information resources contributes to challenging patient and family journeys during the diagnostic period following abnormal NBS results. Patient and Public Involvement and Engagement (PPIE) activities, including parental involvement in paediatrics, are valuable initiatives to improve clinical communication and parental information strategies. Parents of infants with suspected athymia were therefore invited to discuss the information they received during the diagnostic period following NBS with the aim to identify parental information needs and targeted strategies to address these adequately. Parents reported that athymia was not considered with them as a possible differential diagnosis until weeks after initial NBS results. Whilst appropriate clinical information about athymia and TT was available upon referral to specialist immunology services, improved access to easy-to-understand information from reliable sources, including from clinical nurse specialists and peer support systems, remained desirable. A roadmap concept, with written or digital information, addressing parental needs in real time during a potentially complex diagnostic journey, was proposed and is transferrable to other inborn errors of immunity (IEI) and rare diseases. This PPIE activity provides insight into the information needs of parents of infants with suspected athymia who are identified through SCID NBS, and highlights the role for PPIE in promoting patient- and family-centred strategies to improve IEI care.


Assuntos
Síndromes de Imunodeficiência , Imunodeficiência Combinada Severa , Timo/anormalidades , Lactente , Recém-Nascido , Humanos , Criança , Triagem Neonatal , Pais , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia
9.
Elife ; 122024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38466627

RESUMO

Thymus medulla epithelium establishes immune self-tolerance and comprises diverse cellular subsets. Functionally relevant medullary thymic epithelial cells (mTECs) include a self-antigen-displaying subset that exhibits genome-wide promiscuous gene expression promoted by the nuclear protein Aire and that resembles a mosaic of extrathymic cells including mucosal tuft cells. An additional mTEC subset produces the chemokine CCL21, thereby attracting positively selected thymocytes from the cortex to the medulla. Both self-antigen-displaying and thymocyte-attracting mTEC subsets are essential for self-tolerance. Here, we identify a developmental pathway by which mTECs gain their diversity in functionally distinct subsets. We show that CCL21-expressing mTECs arise early during thymus ontogeny in mice. Fate-mapping analysis reveals that self-antigen-displaying mTECs, including Aire-expressing mTECs and thymic tuft cells, are derived from CCL21-expressing cells. The differentiation capability of CCL21-expressing embryonic mTECs is verified in reaggregate thymus experiments. These results indicate that CCL21-expressing embryonic mTECs carry a developmental potential to give rise to self-antigen-displaying mTECs, revealing that the sequential conversion of thymocyte-attracting subset into self-antigen-displaying subset serves to assemble functional diversity in the thymus medulla epithelium.


Assuntos
Timócitos , Fatores de Transcrição , Camundongos , Animais , Timócitos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Camundongos Endogâmicos C57BL , Timo/metabolismo , Diferenciação Celular , Células Epiteliais/metabolismo , Epitélio/metabolismo
10.
Front Immunol ; 15: 1327784, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38455040

RESUMO

Type I interferons (IFN-I) are key immune messenger molecules that play an important role in viral defense. They act as a bridge between microbe sensing, immune function magnitude, and adaptive immunity to fight infections, and they must therefore be tightly regulated. It has become increasingly evident that thymic irregularities and mutations in immune genes affecting thymic tolerance can lead to the production of IFN-I autoantibodies (autoAbs). Whether these biomarkers affect the immune system or tissue integrity of the host is still controversial, but new data show that IFN-I autoAbs may increase susceptibility to severe disease caused by certain viruses, including SARS-CoV-2, herpes zoster, and varicella pneumonia. In this article, we will elaborate on disorders that have been identified with IFN-I autoAbs, discuss models of how tolerance to IFN-Is is lost, and explain the consequences for the host.


Assuntos
Autoanticorpos , Interferon Tipo I , Timo , Herpesvirus Humano 3
11.
JCI Insight ; 9(5)2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38341270

RESUMO

Tregs can facilitate transplant tolerance and attenuate autoimmune and inflammatory diseases. Therefore, it is clinically relevant to stimulate Treg expansion and function in vivo and to create therapeutic Treg products in vitro. We report that TNF receptor 2 (TNFR2) is a unique costimulus for naive, thymus-derived Tregs (tTregs) from human blood that promotes their differentiation into nonlymphoid tissue-resident (NLT-resident) effector Tregs, without Th-like polarization. In contrast, CD28 costimulation maintains a lymphoid tissue-resident (LT-resident) Treg phenotype. We base this conclusion on transcriptome and proteome analysis of TNFR2- and CD28-costimulated CD4+ tTregs and conventional T cells (Tconvs), followed by bioinformatic comparison with published transcriptomic Treg signatures from NLT and LT in health and disease, including autoimmunity and cancer. These analyses illuminate that TNFR2 costimulation promoted tTreg capacity for survival, migration, immunosuppression, and tissue regeneration. Functional studies confirmed improved migratory ability of TNFR2-costimulated tTregs. Flow cytometry validated the presence of the TNFR2-driven tTreg signature in effector/memory Tregs from the human placenta, as opposed to blood. Thus, TNFR2 can be exploited as a driver of NLT-resident tTreg differentiation for adoptive cell therapy or antibody-based immunomodulation in human disease.


Assuntos
Receptores Tipo II do Fator de Necrose Tumoral , Linfócitos T Reguladores , Humanos , Antígenos CD28 , Linfócitos , Timo
12.
Int J Mol Sci ; 25(3)2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38338689

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is a hematological cancer characterized by the infiltration of immature T-cells in the bone marrow. Aberrant NOTCH signaling in T-ALL is mainly triggered by activating mutations of NOTCH1 and overexpression of NOTCH3, and rarely is it linked to NOTCH3-activating mutations. Besides the known critical role of NOTCH, the nature of intrathymic microenvironment-dependent mechanisms able to render immature thymocytes, presumably pre-leukemic cells, capable of escaping thymus retention and infiltrating the bone marrow is still unclear. An important challenge is understanding how leukemic cells shape their tumor microenvironment to increase their ability to infiltrate and survive within. Our previous data indicated that hyperactive NOTCH3 affects the CXCL12/CXCR4 system and may interfere with T-cell/stroma interactions within the thymus. This study aims to identify the biological effects of the reciprocal interactions between human leukemic cell lines and thymic epithelial cell (TEC)-derived soluble factors in modulating NOTCH signaling and survival programs of T-ALL cells and TECs. The overarching hypothesis is that this crosstalk can influence the progressive stages of T-cell development driving T-cell leukemia. Thus, we investigated the effect of extracellular space conditioned by T-ALL cell lines (Jurkat, TALL1, and Loucy) and TECs and studied their reciprocal regulation of cell cycle and survival. In support, we also detected metabolic changes as potential drivers of leukemic cell survival. Our studies could shed light on T-cell/stroma crosstalk to human leukemic cells and propose our culture system to test pharmacological treatment for T-ALL.


Assuntos
Leucemia de Células T , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Timo/metabolismo , Transdução de Sinais , Células Epiteliais/metabolismo , Leucemia de Células T/metabolismo , Apoptose , Proliferação de Células , Microambiente Tumoral
13.
Nature ; 627(8003): 407-415, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38383779

RESUMO

Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen1. The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP42. However, the T cell response that is required for the generation of these anti-AQP4 antibodies is not well understood. Here we show that B cells endogenously express AQP4 in response to activation with anti-CD40 and IL-21 and are able to present their endogenous AQP4 to T cells with an AQP4-specific T cell receptor (TCR). A population of thymic B cells emulates a CD40-stimulated B cell transcriptome, including AQP4 (in mice and humans), and efficiently purges the thymic TCR repertoire of AQP4-reactive clones. Genetic ablation of Aqp4 in B cells rescues AQP4-specific TCRs despite sufficient expression of AQP4 in medullary thymic epithelial cells, and B-cell-conditional AQP4-deficient mice are fully competent to raise AQP4-specific antibodies in productive germinal-centre responses. Thus, the negative selection of AQP4-specific thymocytes is dependent on the expression and presentation of AQP4 by thymic B cells. As AQP4 is expressed in B cells in a CD40-dependent (but not AIRE-dependent) manner, we propose that thymic B cells might tolerize against a group of germinal-centre-associated antigens, including disease-relevant autoantigens such as AQP4.


Assuntos
Aquaporina 4 , Autoanticorpos , Autoantígenos , Linfócitos B , Tolerância Imunológica , Neuromielite Óptica , Animais , Humanos , Camundongos , Aquaporina 4/deficiência , Aquaporina 4/genética , Aquaporina 4/imunologia , Aquaporina 4/metabolismo , Autoanticorpos/imunologia , Autoantígenos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Antígenos CD40/imunologia , Centro Germinativo/citologia , Centro Germinativo/imunologia , Neuromielite Óptica/imunologia , Neuromielite Óptica/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Timo/citologia , Timo/imunologia , Células Epiteliais da Tireoide/imunologia , Células Epiteliais da Tireoide/metabolismo , Transcriptoma
14.
Arkh Patol ; 86(1): 13-20, 2024.
Artigo em Russo | MEDLINE | ID: mdl-38319267

RESUMO

OBJECTIVE: To study morphological features of Hassall's corpuscles (HC) and their microenvironment in newborns with increased thymus mass. MATERIAL AND METHODS: The study was carried out on autopsy material of children of the first month of life. Based on the thymic index (TI), 2 groups were identified: with normal (conditional norm) and increased TI value (increased thymus weight). The standard method of histological staining and immunohistochemical methods with antibodies to Pan-CK, CK19, CD68, CD3 and p53 were used in the study. The classification proposed by A.G. Beloveshkin (2013) was used to determine the degree of maturity of HC. Nonparametric Mann-Whitney test was used to determine statistically significant differences in the groups. RESULTS: In the group of children with increased thymus weight, the number of HC decreased by 20%. It was found that the proportion of progressive and mature corpuscles in this group was reduced by 2.3 and 1.6 times, respectively, compared to the group of children with normal thymus weight, while the proportion of regressive corpuscles increased almost 2-fold. In the HC microenvironment, there is an increase in the total number of thymocytes, combined with a decrease in the expression of CD68, CD3 and p53 in them. A sharp decrease in CK19-expressing cells in this group is accompanied by a disruption in the formation of reticular structures characteristic of the comparison group. CONCLUSION: In the thymus with increased mass, the structural and functional organization changes: along with an increase in the total number of thymocytes in the cortical layer and a decrease in the number of macrophages, epithelial cells and HC (with a predominance of regressive corpuscles), disturbances in the processes of maturation, apoptosis and negative selection of lymphocytes occur, which can lead to development of immunogenesis disorders.


Assuntos
Timo , Proteína Supressora de Tumor p53 , Recém-Nascido , Criança , Humanos , Células Epiteliais , Apoptose , Autopsia
15.
J Clin Immunol ; 44(3): 69, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38393459

RESUMO

Congenital heart disease (CHD) is the most common birth defect, and up to 50% of infants with CHD require cardiovascular surgery early in life. Current clinical practice often involves thymus resection during cardiac surgery, detrimentally affecting T-cell immunity. However, epidemiological data indicate that CHD patients face an elevated risk for infections and immune-mediated diseases, independent of thymectomy. Hence, we examined whether the cardiac defect impacts thymus function in individuals with CHD. We investigated thymocyte development in 58 infants categorized by CHD complexity. To assess the relationship between CHD complexity and thymic function, we analyzed T-cell development, thymic output, and biomarkers linked to cardiac defects, stress, or inflammation. Patients with highly complex CHD exhibit thymic atrophy, resulting in low frequencies of recent thymic emigrants in peripheral blood, even prior to thymectomy. Elevated plasma cortisol levels were detected in all CHD patients, while high NT-proBNP and IL-6 levels were associated with thymic atrophy. Our findings reveal an association between complex CHD and thymic atrophy, resulting in reduced thymic output. Consequently, thymus preservation during cardiovascular surgery could significantly enhance immune function and the long-term health of CHD patients.


Assuntos
Cardiopatias Congênitas , Timo , Lactente , Humanos , Linfócitos T , Cardiopatias Congênitas/cirurgia , Cardiopatias Congênitas/patologia , Atrofia/patologia
16.
Front Immunol ; 15: 1322214, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38318192

RESUMO

Thymus is the main immune organ which is responsible for the production of self-tolerant and functional T cells, but it shrinks rapidly with age after birth. Although studies have researched thymus development and involution in mouse, the critical regulators that arise with age in human thymus remain unclear. We collected public human single-cell transcriptomic sequencing (scRNA-seq) datasets containing 350,678 cells from 36 samples, integrated them as a cell atlas of human thymus. Clinical samples were collected and experiments were performed for validation. We found early thymocyte-specific signaling and regulons which played roles in thymocyte migration, proliferation, apoptosis and differentiation. Nevertheless, signaling patterns including number, strength and path completely changed during aging, Transcription factors (FOXC1, MXI1, KLF9, NFIL3) and their target gene, IGFBP5, were resolved and up-regulated in aging thymus and involved in promoting epithelial-mesenchymal transition (EMT), responding to steroid and adipogenesis process of thymic epithelial cell (TECs). Furthermore, we validated that IGFBP5 protein increased at TECs and Hassall's corpuscle in both human and mouse aging thymus and knockdown of IGFBP5 significantly increased the expression of proliferation-related genes in thymocytes. Collectively, we systematically explored cell-cell communications and regulons of early thymocytes as well as age-related differences in human thymus by using both bioinformatic and experimental verification, indicating IGFBP5 as a functional marker of thymic involution and providing new insights into the mechanisms of thymus involution.


Assuntos
Envelhecimento , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina , Timócitos , Timo , Humanos , Envelhecimento/genética , Diferenciação Celular/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Transdução de Sinais , Timócitos/metabolismo , Timo/metabolismo , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/genética
17.
Immunol Rev ; 322(1): 178-211, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38228406

RESUMO

The thymus is the primary site of T-cell development, enabling generation, and selection of a diverse repertoire of T cells that recognize non-self, whilst remaining tolerant to self- antigens. Severe congenital disorders of thymic development (athymia) can be fatal if left untreated due to infections, and thymic tissue implantation is the only cure. While newborn screening for severe combined immune deficiency has allowed improved detection at birth of congenital athymia, thymic disorders acquired later in life are still underrecognized and assessing the quality of thymic function in such conditions remains a challenge. The thymus is sensitive to injury elicited from a variety of endogenous and exogenous factors, and its self-renewal capacity decreases with age. Secondary and age-related forms of thymic dysfunction may lead to an increased risk of infections, malignancy, and autoimmunity. Promising results have been obtained in preclinical models and clinical trials upon administration of soluble factors promoting thymic regeneration, but to date no therapy is approved for clinical use. In this review we provide a background on thymus development, function, and age-related involution. We discuss disease mechanisms, diagnostic, and therapeutic approaches for primary and secondary thymic defects.


Assuntos
Síndromes de Imunodeficiência , Linfócitos T , Timo/anormalidades , Recém-Nascido , Humanos , Diferenciação Celular
18.
Gen Comp Endocrinol ; 348: 114448, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38191062

RESUMO

The thymus is an energy-consuming organ, and its metabolism changes with atrophy. Testosterone regulates thymus remodeling (atrophy and regeneration). However, the characteristics of the energy metabolism during testosterone-mediated thymic atrophy and regeneration remain unclear. In this study, we demonstrated that testosterone ablation (implemented by immunocastration and surgical castration) induced global metabolic changes in the thymus. Kyoto Encyclopedia of Genes and Genomes pathway enrichment for differential metabolites and metabolite set enrichment analysis for total metabolites revealed that testosterone ablation affected thymic glycolysis, glutamate metabolism, and fatty acid ß-oxidation. Testosterone ablation-induced thymic regeneration was accompanied by attenuated glycolysis and glutamate metabolism and changed fatty acid composition and content. Testosterone supplementation in immunocastrated and surgically castrated rats enhanced glutaminolysis, reduced the level of unsaturated fatty acids, enhanced the ß-oxidation of unsaturated fatty acids in the mitochondria, boosted the tricarboxylic acid (TCA) cycle, and accelerated thymic atrophy. Overall, these results imply that metabolic reprogramming is directly related to thymic remodeling.


Assuntos
Testosterona , Ratos , Animais , Masculino , Testosterona/metabolismo , Timo , Orquiectomia , Ácidos Graxos Insaturados/metabolismo , Atrofia/metabolismo , Ácidos Graxos/metabolismo , Glutamatos/metabolismo
20.
Nat Immunol ; 25(1): 54-65, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38062135

RESUMO

The nature of activation signals is essential in determining T cell subset differentiation; however, the features that determine T cell subset preference acquired during intrathymic development remain elusive. Here we show that naive CD4+ T cells generated in the mouse thymic microenvironment lacking Scd1, encoding the enzyme catalyzing oleic acid (OA) production, exhibit enhanced regulatory T (Treg) cell differentiation and attenuated development of experimental autoimmune encephalomyelitis. Scd1 deletion in K14+ thymic epithelia recapitulated the enhanced Treg cell differentiation phenotype of Scd1-deficient mice. The dearth of OA permitted DOT1L to increase H3K79me2 levels at the Atp2a2 locus of thymocytes at the DN2-DN3 transition stage. Such epigenetic modification persisted in naive CD4+ T cells and facilitated Atp2a2 expression. Upon T cell receptor activation, ATP2A2 enhanced the activity of the calcium-NFAT1-Foxp3 axis to promote naive CD4+ T cells to differentiate into Treg cells. Therefore, OA availability is critical for preprogramming thymocytes with Treg cell differentiation propensities in the periphery.


Assuntos
Ácido Oleico , Timócitos , Animais , Camundongos , Ácido Oleico/metabolismo , Timo , Linfócitos T Reguladores , Diferenciação Celular , Fatores de Transcrição Forkhead/genética
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