Thymic homing of activated CD4+ T cells induces degeneration of the thymic epithelium through excessive RANK signaling

Yin, Chuancun; Pei, Xiao-Yan; Shen, Hui; Gao, Yanan; Sun, Xiuyuan; Wang, Wei; Ge, Qing

doi:10.1038/s41598-017-02653-9

Cited by 25 publications

(21 citation statements)

References 57 publications

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“…Notably, Aire- deficient mice contained a significantly higher percentage of IFN-γ-producing Th1 cells. This is consistent with the previous finding that APS1 is predominantly a Th1-mediated disorder [35].…”

Section: Resultssupporting

confidence: 94%

“…The accumulation of these Th1 cells in the thymus was closely associated with reduced thymocyte numbers and thymic output and increased senescent epithelial cells in these mouse models. Consistently, patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, a human form of Aire mutation) also have Th1-biased cytokine profile [35], suggesting that Th1 cells contribute to accelerated thymic aging in this specific autoimmune disorder. In addition, the impact of IFN-γ on senescence is not limited to thymic epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

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Th1 Biased Progressive Autoimmunity in Aged Aire-Deficient Mice Accelerated Thymic Epithelial Cell Senescence

et al. 2019

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Although autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, are frequently associated with premature aging of the thymus, a direct link is missing between autoimmunity and thymic atrophy. Here we monitored the progression of thymic involution in Aire- deficient mice, in which defective negative selection causes spontaneous and progressive development of autoimmunity. In young and middle-aged mice, Aire deficiency appeared to be protective as supported by the reduced β-gal + epithelial cells and the enhanced thymic output. However, once the autoimmune phenotype was fully developed in aged Aire- deficient mice, their thymuses underwent accelerated involution. In comparison to the age-matched wildtype littermates, old Aire- deficient mice showed lower numbers of total thymocytes and recent thymic emigrants but more β-gal + thymic epithelial cells. This phenomenon may partly be attributable to the increased number of activated Th1 cells homing to the thymus. This speculation was further supported by the enhanced thymic aging following repeated challenges with complete Freund’s adjuvant immunization. Taken together, the present study highlights a unique mechanism by which autoimmunity facilitates the senescence of thymic epithelial cells through returning Th1 cells.

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Section: Resultssupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Th1 Biased Progressive Autoimmunity in Aged Aire-Deficient Mice Accelerated Thymic Epithelial Cell Senescence

et al. 2019

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“… 36 According to a previous report, coculturing a fetal thymus with activated CD4 + T cells produced a significant inhibitory effect on T-cell development by inducing structural and functional abnormalities in TECs. 37 These findings suggest that the expression of CD147 on activated CD4 + T cells may induce the EMT process in TECs. Therefore, we sorted CD4 + CD44-CD62L + T cells obtained from the CD45.1 + mice and cultured them in vitro with anti-CD3/CD28 antibodies.…”

Section: Resultsmentioning

confidence: 85%

CD147 deficiency in T cells prevents thymic involution by inhibiting the EMT process in TECs in the presence of TGFβ

et al. 2020

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Thymic involution during aging is a major cause of decreased T-cell production and reduced immunity. Here, we show that the loss of CD147 on T cells prevents thymic senescence, resulting in slowed shrinkage of the thymus with age and increased production of naive T cells. This phenotype is the result of slowing of the epithelial–mesenchymal transition (EMT) process in thymic epithelial cells (TECs), which eventually leads to reduced adipocyte accumulation. In an in vitro coculture system, we found that TGFβ is an important factor in the EMT process in TECs and that it can reduce the expression of E-cadherin through p-Smad2/FoxC2 signaling. Moreover, CD147 on T cells can accelerate the decline in E-cadherin expression by interacting with Annexin A2 on TECs. In the presence of TGFβ, Annexin A2 and E-cadherin colocalize on TECs. However, CD147 on T cells competitively binds to Annexin A2 on TECs, leading to the isolation of E-cadherin. Then, the isolated E-cadherin is easily phosphorylated by phosphorylated Src kinase, the phosphorylation of which was induced by TGFβ, and finally, p-E-cadherin is degraded. Thus, in the thymus, the interaction between T cells and TECs contributes to thymic involution with age. In this study, we illuminate the mechanism underlying the triggering of the EMT process in TECs and show that inhibiting TGFβ and/or CD147 may serve as a strategy to hinder age-related thymic involution.

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“…Transgenic mice expressing Venus, a fluorescent protein to track RANK expression, showed that this receptor is mainly expressed by mTECs at different stages of differentiation (90). Moreover, activated T cells recirculating to the thymus further contribute to the production of RANKL (91). Thus, it is tempting to speculate that the increased production of RANKL may support the skewing toward mTEC lineage, with consequent maturation of T cells leading to the exhaustion of the progenitor pool.…”

Section: Rankl-rank Axis In the Thymusmentioning

confidence: 99%

The RANKL-RANK Axis: A Bone to Thymus Round Trip

2019

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The identification of Receptor activator of nuclear factor kappa B ligand (RANKL) and its cognate receptor Receptor activator of nuclear factor kappa B (RANK) during a search for novel tumor necrosis factor receptor (TNFR) superfamily members has dramatically changed the scenario of bone biology by providing the functional and biochemical proof that RANKL signaling via RANK is the master factor for osteoclastogenesis. In parallel, two independent studies reported the identification of mouse RANKL on activated T cells and of a ligand for osteoprotegerin on a murine bone marrow-derived stromal cell line. After these seminal findings, accumulating data indicated RANKL and RANK not only as essential players for the development and activation of osteoclasts, but also for the correct differentiation of medullary thymic epithelial cells (mTECs) that act as mediators of the central tolerance process by which self-reactive T cells are eliminated while regulatory T cells are generated. In light of the RANKL-RANK multi-task function, an antibody targeting this pathway, denosumab, is now commonly used in the therapy of bone loss diseases including chronic inflammatory bone disorders and osteolytic bone metastases; furthermore, preclinical data support the therapeutic application of denosumab in the framework of a broader spectrum of tumors. Here, we discuss advances in cellular and molecular mechanisms elicited by RANKL-RANK pathway in the bone and thymus, and the extent to which its inhibition or augmentation can be translated in the clinical arena.

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Thymic homing of activated CD4+ T cells induces degeneration of the thymic epithelium through excessive RANK signaling

Cited by 25 publications

References 57 publications

Th1 Biased Progressive Autoimmunity in Aged Aire-Deficient Mice Accelerated Thymic Epithelial Cell Senescence

Th1 Biased Progressive Autoimmunity in Aged Aire-Deficient Mice Accelerated Thymic Epithelial Cell Senescence

CD147 deficiency in T cells prevents thymic involution by inhibiting the EMT process in TECs in the presence of TGFβ

The RANKL-RANK Axis: A Bone to Thymus Round Trip

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