Thymus machinery for T-cell selection

Kondo, Kenta; Ohigashi, Izumi; Takahama, Yousuke

doi:10.1093/intimm/dxy081

Cited by 69 publications

(56 citation statements)

References 127 publications

(130 reference statements)

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“…In the thymic cortex, a predominant positive selection process leads thymocytes to differentiate from the double-negative CD4-CD8-stage to the double-positive (DP) CD4þCD8þ stage. Double-positive thymocytes enter the thymic medulla to undergo a negative selection process (18) . At this stage, medullary thymic epithelial cells orchestrate the presentation of antigens from virtually all organs to maturing thymocytes via MHC type II molecules expressed on thymic dendritic cells (19) .…”

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confidence: 99%

Intra-uterine growth restriction induced by maternal low-protein diet causes long-term alterations of thymic structure and function in adult male rat offspring

et al. 2020

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Early malnutrition, the first environmental cause of intra-uterine growth restriction, impairs development of the thymus. Alterations of the thymic structure and function are reported at young ages in murine and ovine models. However, descriptions of thymic consequences of fetal malnutrition at adulthood are scarce. The present study investigates thymic structure, protein expression and cell selection process observed at postnatal day 180 (PND180) in male offspring of rats exposed to maternal low-protein diet (mLPD) compared with control diet during gestation. The thymic index was lower in adult offspring exposed to mLPD (P < 0·05). The thymic cortico-medullar ratio was lower in adult offspring exposed to mLPD (P < 0·05). At PND180, the protein expression of the lymphotoxin β receptor (P < 0·05), the autoimmune regulator (P < 0·05) and Forkhead Box P3 (FoxP3; P < 0·05) was all significantly lower in the mLPD group. The CD4+:CD8+ single-positive thymocyte subpopulation ratio and CD4+:CD8+ lymphocyte subpopulation ratio were increased in the mLPD group (P < 0·05). Among CD3+ lymphocytes, the proportions of CD4+CD8+ double-positive lymphocytes, CD31+ recent thymic emigrants and CD4+FoxP3+ lymphocytes were not significantly different between mLPD and control groups. These findings suggest mLPD during gestation induced long-lasting alterations in the development of thymic structure and thymic cell maturation and selection process in adult male rat offspring.

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confidence: 99%

Intra-uterine growth restriction induced by maternal low-protein diet causes long-term alterations of thymic structure and function in adult male rat offspring

et al. 2020

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“…The differentiation of CD4 − CD8 − CD3 − (TN) thymocytes has been historically divided into four subsets on the basis of CD44 and CD25 expression, with TN1, TN2, TN3 and TN4 subsets defined as CD44 + CD25 − , CD44 + CD25 + , CD44 − CD25 + and CD44 − CD25 − , respectively ( 1 , 2 , 4 ). Given the heterogeneity of PiT2 expression in the DN thymocyte subsets ( Figure 1A ), we specifically evaluated PiT2 levels in each of the TN subsets.…”

Section: Resultsmentioning

confidence: 99%

“…The thymus is critical for the differentiation of T lymphocytes, promoting the generation of a pool of functionally competent T cells that provide protection against pathogens and tumors while maintaining self-tolerance. T cell differentiation in the thymus arises from progenitor cells that are derived from bone marrow hematopoietic stem cells (HSC) [reviewed in (1)(2)(3)(4)(5)]. Once progenitor cells enter into the thymus, the thymic environment generally results in their acquisition of a shortlived T cell precursor phenotype [as has been previously shown for common lymphocyte progenitors; (6,7)].…”

Section: Introductionmentioning

confidence: 99%

Phosphate Transporter Profiles in Murine and Human Thymi Identify Thymocytes at Distinct Stages of Differentiation

et al. 2020

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Thymocyte differentiation is dependent on the availability and transport of metabolites in the thymus niche. As expression of metabolite transporters is a rate-limiting step in nutrient utilization, cell surface transporter levels generally reflect the cell's metabolic state. The GLUT1 glucose transporter is upregulated on actively dividing thymocytes, identifying thymocytes with an increased metabolism. However, it is not clear whether transporters of essential elements such as phosphate are modulated during thymocyte differentiation. While PiT1 and PiT2 are both phosphate transporters in the SLC20 family, we show here that they exhibit distinct expression profiles on both murine and human thymocytes. PiT2 expression distinguishes thymocytes with high metabolic activity, identifying immature murine double negative (CD4 − CD8 −) DN3b and DN4 thymocyte blasts as well as immature single positive (ISP) CD8 thymocytes. Notably, the absence of PiT2 expression on RAG2-deficient thymocytes, blocked at the DN3a stage, strongly suggests that high PiT2 expression is restricted to thymocytes having undergone a productive TCRβ rearrangement at the DN3a/DN3b transition. Similarly, in the human thymus, PiT2 was upregulated on early post-β selection CD4 + ISP and TCRαβ − CD4 hi DP thymocytes co-expressing the CD71 transferrin receptor, a marker of metabolic activity. In marked contrast, expression of the PiT1 phosphate importer was detected on mature CD3 + murine and human thymocytes. Notably, PiT1 expression on CD3 + DN thymocytes was identified as a biomarker of an aging thymus, increasing from 8.4 ± 1.5% to 42.4 ± 9.4% by 1 year of age (p < 0.0001). We identified these cells as TCRγδ and, most significantly, NKT, representing 77 ± 9% of PiT1 + DN thymocytes by 1 year of age (p < 0.001). Thus, metabolic activity and thymic aging are associated with distinct expression profiles of the PiT1 and PiT2 phosphate transporters.

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“…CDR2 has been found to be poorly immunogenic even when expressed in tumors (107,108). During lymphocytes development in the thymus, tolerance mechanisms delete most autoreactive T cells with high affinity or redirect them to a regulatory phenotype (109,110). Through "ectopic" expression of a number of tissue-associated self-antigens, the autoimmune regulator (AIRE) acts as a master regulator of central T-cell tolerance by preventing the development of pathogenic autoreactive T cells (111,112).…”

Section: Immune Tolerance and Pcdmentioning

confidence: 99%

Immunological Bases of Paraneoplastic Cerebellar Degeneration and Therapeutic Implications

2020

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Paraneoplastic cerebellar degeneration (PCD) is a rare immune-mediated disease that develops mostly in the setting of neoplasia and offers a unique prospect to explore the interplay between tumor immunity and autoimmunity. In PCD, the deleterious adaptive immune response targets self-antigens aberrantly expressed by tumor cells, mostly gynecological cancers, and physiologically expressed by the Purkinje neurons of the cerebellum. Highly specific anti-neuronal antibodies in the serum and cerebrospinal fluid represent key diagnostic biomarkers of PCD. Some anti-neuronal antibodies such as anti-Yo autoantibodies (recognizing the CDR2/CDR2L proteins) are only associated with PCD. Other anti-neuronal antibodies, such as anti-Hu, anti-Ri, and anti-Ma2, are detected in patients with PCD or other types of paraneoplastic neurological manifestations. Importantly, these autoantibodies cannot transfer disease and evidence for a pathogenic role of autoreactive T cells is accumulating. However, the precise mechanisms responsible for disruption of self-tolerance to neuronal self-antigens in the cancer setting and the pathways involved in pathogenesis within the cerebellum remain to be fully deciphered. Although the occurrence of PCD is rare, the risk for such severe complication may increase with wider use of cancer immunotherapy, notably immune checkpoint blockade. Here, we review recent literature pertaining to the pathophysiology of PCD and propose an immune scheme underlying this disabling disease. Additionally, based on observations from patients' samples and on the pre-clinical model we recently developed, we discuss potential therapeutic strategies that could blunt this cerebellum-specific autoimmune disease.

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Thymus machinery for T-cell selection

Cited by 69 publications

References 127 publications

Intra-uterine growth restriction induced by maternal low-protein diet causes long-term alterations of thymic structure and function in adult male rat offspring

Intra-uterine growth restriction induced by maternal low-protein diet causes long-term alterations of thymic structure and function in adult male rat offspring

Phosphate Transporter Profiles in Murine and Human Thymi Identify Thymocytes at Distinct Stages of Differentiation

Immunological Bases of Paraneoplastic Cerebellar Degeneration and Therapeutic Implications

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