Medullary thymic epithelial stem cells: role in thymic epithelial cell maintenance and thymic involution

Hamazaki, Yoko; Sekai, Miho; Minato, Nagahiro

doi:10.1111/imr.12412

Cited by 48 publications

(43 citation statements)

References 178 publications

(338 reference statements)

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“…Not surprisingly, α6 hi Sca-1 hi mTEC lo do not fall within the mTEC-II phenotype which express Aire and other mature mTEC markers (45). Further research is, however, required to establish the link between α6 hi Sca-1 hi mTEC lo and previously identified postnatal mTEC progenitor phenotypes such as stage-specific embryonic antigen-1 (SSEA-1) + Claudin (Cld)3,4 hi TECs (46,47). Given that gender disparity was observed in our aging studies, we compared the regenerative effect of LHRH receptorantagonist, degarelix, on the middle-aged female thymus to their male counterparts.…”

Section: Discussionmentioning

confidence: 92%

Gender Disparity Impacts on Thymus Aging and LHRH Receptor Antagonist-Induced Thymic Reconstitution Following Chemotherapeutic Damage

et al. 2020

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One of the main consequences of thymus aging is the decrease in naïve T cell output. This condition accelerates at the onset of puberty, and presents as a major clinical complication for cancer patients who require cytoablative therapy. Specifically, the extensive use of chemotherapeutics, such as cyclophosphamide, in such treatments damage thymic structure and eliminate the existing naïve T cell repertoire. The resulting immunodeficiency can lead to increased incidence of opportunistic infections, tumor growth relapse and/or autoimmune diseases, particularly in older patients. Thus, strategies aimed at rejuvenating the aged thymus following chemotherapeutic damage are required. Previous studies have revealed that sex hormone deprivation in male mice is capable of regenerating the thymic microenvironment following chemotherapy treatment, however, further investigation is crucial to identify gender-based differences, and the molecular mechanisms involved during thymus regeneration. Through phenotypic analyzes, we identified gender-specific alterations in thymocytes and thymic epithelial cell (TEC) subsets from the onset of puberty. By middle-age, females presented with a higher number of thymocytes in comparison to males, yet a decrease in their Aire + medullary TEC/thymocyte ratio was observed. This reduction could be associated with an increased risk of autoimmune disease in middle-aged women. Given the concurrent increase in female Aire + cTEC/thymocyte ratio, we proposed that there may be an impediment in Aire + mTEC hi differentiation, and Aire + cTEC hi as its upstream precursor. The regenerative effects of LHRH receptor antagonist, degarelix, on TEC subsets was also less pronounced in middle-aged females compared to males, possibly due to slower progression of thymic involution in the former, which presented with greater TEC hi proportions. Furthermore, following cyclophosphamide treatment, degarelix enhanced thymocyte and mature TEC subset recovery, with faster recovery kinetics observed in females. These events were found to involve both reactivation and proliferation of thymic epithelial progenitor cells. Taken together, the findings from this study portray Hun et al. Gender Disparity in the Aging Thymus a relationship between gender disparity and thymus aging, and highlight the potential benefits of LHRH receptor antagonist treatment for thymic regeneration. Further research is required, however, to determine how gender may impact on the mechanisms underpinning these events.

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Section: Discussionmentioning

confidence: 92%

Gender Disparity Impacts on Thymus Aging and LHRH Receptor Antagonist-Induced Thymic Reconstitution Following Chemotherapeutic Damage

et al. 2020

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“…Histological analysis of unseeded control lobes showed a tissue architecture characterized by an astrocyte-like thymic epithelial web (Hamazaki et al, 2016) but no CD3 + cells. When seeded with iPSC-derived immature T cells, the tissue was repopulated with CD3 + mononuclear cells (Figure 2C).…”

Section: Resultsmentioning

confidence: 99%

Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System

et al. 2018

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SUMMARY Induced pluripotent stem cell (iPSC)-derived T cells may provide future therapies for cancer patients, but those generated by current methods, such as the OP9/DLL1 system, have shown abnormalities that pose major barriers for clinical translation. Our data indicate that these iPSC-derived CD8 single-positive T cells are more like CD4+CD8+ double-positive T cells than mature naive T cells because they display phenotypic markers of developmental arrest and an innate-like phenotype after stimulation. We developed a 3D thymic culture system to avoid these aberrant developmental fates, generating a homogeneous subset of CD8ab+ antigen-specific T cells, designated iPSC-derived thymic emigrants (iTEs). iTEs exhibit phenotypic and functional similarities to naive T cells both in vitro and in vivo, including the capacity for expansion, memory formation, and tumor suppression. These data illustrate the limitations of current methods and provide a tool to develop the next generation of iPSC-based antigen-specific immunotherapies.

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“…This is potentially very interesting. In support of this, the Immgen database indicates that medullary epithelial cells (MECs), which are involved in positive selection in the thymus, express Cxcl17 (data not shown). This raises the possibility that positive selection of T cells in the thymus of Cxcl17 −/‐ mouse may be abnormal, suggesting that it may be uniquely susceptible to autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Cxcl17 -/- mice develop exacerbated disease in a T cell-dependent autoimmune model

Hernández‐Ruiz

Othy

Herrera

et al. 2019

Journal of Leukocyte Biology

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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.

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Medullary thymic epithelial stem cells: role in thymic epithelial cell maintenance and thymic involution

Cited by 48 publications

References 178 publications

Gender Disparity Impacts on Thymus Aging and LHRH Receptor Antagonist-Induced Thymic Reconstitution Following Chemotherapeutic Damage

Gender Disparity Impacts on Thymus Aging and LHRH Receptor Antagonist-Induced Thymic Reconstitution Following Chemotherapeutic Damage

Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System

Cxcl17 -/- mice develop exacerbated disease in a T cell-dependent autoimmune model

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