Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution

Age-related thymic degeneration is associated with loss of naïve T cells, restriction of peripheral T-cell diversity, and reduced healthspan due to lower immune competence. The mechanistic basis of age-related thymic demise is unclear, but prior evidence suggests that caloric restriction (CR) can slow thymic aging by maintaining thymic epithelial cell integrity and reducing the generation of intrathymic lipid. Here we show that the prolongevity ketogenic hormone fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily, is expressed in thymic stromal cells along with FGF receptors and its obligate coreceptor, βKlotho. We found that FGF21 expression in thymus declines with age and is induced by CR. Genetic gain of FGF21 function in mice protects against age-related thymic involution with an increase in earliest thymocyte progenitors and cortical thymic epithelial cells. Importantly, FGF21 overexpression reduced intrathymic lipid, increased perithymic brown adipose tissue, and elevated thymic T-cell export and naïve T-cell frequencies in old mice. Conversely, loss of FGF21 function in middle-aged mice accelerated thymic aging, increased lethality, and delayed T-cell reconstitution postirradiation and hematopoietic stem cell transplantation (HSCT). Collectively, FGF21 integrates metabolic and immune systems to prevent thymic injury and may aid in the reestablishment of a diverse T-cell repertoire in cancer patients following HSCT.

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Obesity accelerates thymic aging

Blood ◽

10.1182/blood-2009-03-213595 ◽

2009 ◽

Vol 114 (18) ◽

pp. 3803-3812 ◽

Cited By ~ 149

Author(s):

Hyunwon Yang ◽

Yun-Hee Youm ◽

Bolormaa Vandanmagsar ◽

Jennifer Rood ◽

K. Ganesh Kumar ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Surveillance ◽

Cell Receptor ◽

Effector Memory ◽

Thymic Involution ◽

Cell Repertoire ◽

Diet Induced Obesity ◽

Age Related ◽

Repertoire Diversity

Abstract As the expanding obese population grows older, their successful immunologic aging will be critical to enhancing the health span. Obesity increases risk of infections and cancer, suggesting adverse effects on immune surveillance. Here, we report that obesity compromises the mechanisms regulating T-cell generation by inducing premature thymic involution. Diet-induced obesity reduced thymocyte counts and significantly increased apoptosis of developing T-cell populations. Obesity accelerated the age-related reduction of T-cell receptor (TCR) excision circle bearing peripheral lymphocytes, an index of recently generated T cells from thymus. Consistent with reduced thymopoiesis, dietary obesity led to reduction in peripheral naive T cells with increased frequency of effector-memory cells. Defects in thymopoiesis in obese mice were related with decrease in the lymphoid-primed multipotent progenitor (Lin−Sca1+Kit+ Flt3+) as well as common lymphoid progenitor (Lin−Sca1+CD117loCD127+) pools. The TCR spectratyping analysis showed that obesity compromised V-β TCR repertoire diversity. Furthermore, the obesity induced by melanocortin 4 receptor deficiency also constricted the T-cell repertoire diversity, recapitulating the thymic defects observed with diet-induced obesity. In middle-aged humans, progressive adiposity with or without type 2 diabetes also compromised thymic output. Collectively, these findings establish that obesity constricts T-cell diversity by accelerating age-related thymic involution.

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Mouse embryonic stem cell-derived thymic epithelial cell progenitors enhance T-cell reconstitution after allogeneic bone marrow transplantation

Blood ◽

10.1182/blood-2011-03-340794 ◽

2011 ◽

Vol 118 (12) ◽

pp. 3410-3418 ◽

Cited By ~ 32

Author(s):

Laijun Lai ◽

Cheng Cui ◽

Jingjun Jin ◽

Zhifang Hao ◽

Qiuhong Zheng ◽

...

Keyword(s):

T Cell ◽

Epithelial Cell ◽

Allogeneic Bone Marrow Transplantation ◽

Embryonic Stem ◽

Mouse Embryonic Stem Cell ◽

Thymic Epithelial Cells ◽

Thymic Epithelial Cell ◽

Allogeneic Bone ◽

Thymic Involution

Abstract We have reported that mouse embryonic stem cells (mESCs) can be selectively induced in vitro to differentiate into thymic epithelial cell progenitors (TEPs). When placed in vivo, these mESC-derived TEPs differentiate into cortical and medullary thymic epithelial cells, reconstitute the normal thymic architecture, and enhance thymocyte regeneration after syngeneic BM transplantation (BMT). Here, we show that transplantation of mESC-derived TEPs results in the efficient establishment of thymocyte chimerism and subsequent generation of naive T cells in both young and old recipients of allo-geneic BM transplant. GVHD was not induced, whereas graft-versus-tumor activity was significantly enhanced. Importantly, the reconstituted immune system was tolerant to host, mESC, and BM transplant donor antigens. Therefore, ESC-derived TEPs may offer a new approach for the rapid and durable correction of T-cell immune deficiency after BMT, and the induction of tolerance to ESC-derived tissue and organ transplants. In addition, ESC-derived TEPs may also have use as a means to reverse age-dependent thymic involution, thereby enhancing immune function and decreasing infection rates in the elderly.

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miR-199b-5p enhances the proliferation of medullary thymic epithelial cells via regulating Wnt signaling by targeting Fzd6

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa145 ◽

2020 ◽

Author(s):

Xintong Wang ◽

Ying Li ◽

Bishuang Gong ◽

Kaizhao Zhang ◽

Yongjiang Ma ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Epithelial Cells ◽

Wnt Signaling ◽

Thymic Epithelial Cells ◽

Thymic Epithelial Cell ◽

Thymus Involution ◽

Age Related ◽

Cell Cycle Signaling ◽

Thymic Aging

Abstract Thymic epithelial cells (TECs) are essential regulators of T-cell development and selection. miRNAs play critical roles in regulating TEC proliferation during the process of thymic aging. Our previous studies revealed that miR-199b-5p was upregulated in TECs from 1- to 3-month-old mice. But its function and potential mechanism are not clear. We hypothesized that miR-199b-5p may play an important role in age-related thymus involution via targeting some genes. To confirm it, the murine thymic epithelial cell line 1 (MTEC1) cells were used. Our results showed that overexpression of miR-199b-5p can enhance MTEC1 cell proliferation. On the contrary, repression of miR-199b-5p can inhibit MTEC1 cell proliferation. Meanwhile, it was confirmed that frizzled receptor 6 (Fzd6) is the direct target gene of miR-199b-5p. Furthermore, overexpression of miR-199b-5p can upregulate the expressions of β-catenin, Tcf7, Wnt4, and C-myc to activate Wnt signaling and cell cycle signaling. Silence of Fzd6 and co-transfection with siFzd6 and miR-199b-5p mimic/inhibitor confirmed that the biological function of miR-199b-5p is indeed by targeting Fzd6 in medullary TECs. Overall, miR-199b-5p is an important regulator in medullary TEC proliferation through targeting Fzd6 to activate Wnt signaling and cell cycle signaling. Our data indicate that miR-199b-5p may block the process of thymic aging and be a potential therapeutic target for thymus involution.

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Bone Marrow-Derived Cells Contribute to the Maintenance of Thymic Stroma including Thymic Epithelial Cells

10.1101/2020.09.29.319426 ◽

2020 ◽

Author(s):

Shami Chakrabarti ◽

Mohammed Hoque ◽

Nawshin Zara Jamil ◽

Varan J Singh ◽

Neelab Meer ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Progenitor Cells ◽

Cell Function ◽

Thymic Epithelial Cells ◽

Thymic Epithelial Cell ◽

Cancer Therapies ◽

Thymic Involution ◽

Thymic Tissue ◽

Cell Therapies

AbstractIn paradox to critical functions for T-cell selection and self-tolerance, the thymus undergoes profound age-associated atrophy and loss of T-cell function, which are further enhanced by cancer therapies. Identification of thymic epithelial progenitor populations capable of forming functional thymic tissue will be critical in understanding thymic epithelial cell (TEC) ontogeny and designing strategies to reverse involution. We identified a new population of progenitor cells, present in both thymus and bone marrow (BM), that co-express the hematopoietic marker CD45 and the definitive thymic epithelial marker EpCAM and maintains the capacity to form functional thymic tissue. Confocal analysis and qRT-PCR of sorted cells from both BM and thymus confirmed co-expression of CD45 and EpCAM. Grafting of C57BL/6 fetal thymi under the kidney capsule of H2BGFP transgenic mice revealed that peripheral CD45+ EpCAM+ GFP-expressing cells migrate into the developing thymus and contribute to both TECs and FSP1-expressing stroma. Sorted BM-derived CD45+EpCAM+ cells contribute to reaggregate thymic organ cultures (RTOCs) and differentiate into keratin and FoxN1 expressing TECs, demonstrating that BM cells can contribute to the maintenance of TEC microenvironments previously thought to be derived solely from endoderm. BM-derived CD45+EpCAM+ cells represent a new source of progenitor cells that contribute to thymic homeostasis. Future studies will characterize the contribution of BM-derived CD45+EpCAM+ TEC progenitors to distinct functional TEC microenvironments in both the steady-state thymus and under conditions of demand. Cell therapies utilizing this population may prove useful for counteracting thymic involution in cancer patients.

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

Cellular and Molecular Immunology ◽

10.1038/s41423-019-0353-7 ◽

2020 ◽

Vol 18 (1) ◽

pp. 171-181 ◽

Cited By ~ 3

Author(s):

Ruo Chen ◽

Ke Wang ◽

Zhuan Feng ◽

Ming-Yang Zhang ◽

Jiao Wu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Epithelial Mesenchymal Transition ◽

Annexin A2 ◽

Thymic Epithelial Cells ◽

Thymic Involution ◽

Mesenchymal Transition ◽

Age Related ◽

E Cadherin

AbstractThymic 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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Thymic rejuvenation via induced thymic epithelial cells (iTECs) from FOXN1-overexpressing fibroblasts to counteract inflammaging

10.1101/2020.03.17.995357 ◽

2020 ◽

Author(s):

Jiyoung Oh ◽

Weikan Wang ◽

Rachel Thomas ◽

Dong-Ming Su

Keyword(s):

T Cell ◽

Epithelial Cells ◽

Negative Selection ◽

De Novo ◽

The Elderly ◽

Thymic Epithelial Cells ◽

Thymic Involution ◽

Embryonic Fibroblasts ◽

Central Tolerance ◽

Age Related

AbstractAge-associated systemic, chronic, sterile inflammatory condition (inflammaging) is partially attributed to increased self (auto)-reactivity, resulting from disruption of central tolerance in the aged, involuted thymus. Age-related thymic involution causally results from gradually declined expression of the transcription factor forkhead box N1 (FOXN1) in thymic epithelial cells (TECs), while exogenous FOXN1 in TECs can significantly rescue age-related thymic involution. Given the findings that induced TECs (iTECs) from FOXN1-overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule and intra-thymically injected natural young TECs can lead to middle-aged thymus regrowth, we sought to expand upon these two findings by applying them as a novel thymic rejuvenation strategy with two types of promoter-driven (Rosa26CreERT and FoxN1Cre) Cre-mediated iTECs. We engrafted iTECs, rather than natural young TECs, directly into the aged thymus and/or peri-thymus and found a significantly rejuvenated architecture and function in the native aged murine thymus. The engrafted iTECs drove regrowth of the aged thymus in both male and female mice, showing not only increased thymopoiesis, but also reinforcement of thymocyte negative selection, thereby, reducing senescent T cells and auto-reactive T cell-mediated inflammaging phenotypes in old mice. Therefore, this is a promising thymic rejuvenation strategy with preclinical significance, which can potentially rescue declined thymopoiesis and impaired negative selection to significantly, albeit partially, restore the defective central tolerance and reduce subclinical chronic inflammatory symptoms in the elderly.Graphical AbstractA novel rejuvenation strategy via the FOXN1-TEC axis using induced two types of FOXN1-overexpressing embryonic fibroblasts (termed iTECs) by intrathymic injection is able to counteract age-related thymic involution, which rescued negative selection, thereby, reducing peripheral T cell-associated inflammaging conditions.

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Immunosenescence: potential causes and strategies for reversal

Biochemical Society Transactions ◽

10.1042/bst0280250 ◽

2000 ◽

Vol 28 (2) ◽

pp. 250-254 ◽

Cited By ~ 33

Author(s):

R. Aspinall ◽

D. Andrew

Keyword(s):

T Cell ◽

Immune Dysfunction ◽

Careful Analysis ◽

Experimental Therapy ◽

Thymic Involution ◽

Interleukin 7 ◽

Cell Pool ◽

Age Related ◽

Peripheral T Cells ◽

Laboratory Investigations

Age-related deterioration in immune function has been recognized in many species. In humans the clinical manifestation of such immune dysfunction is age-related increases in the susceptibility to certain infections and in the incidence of some autoimmune disease and certain cancers. Laboratory investigations reveal age-related changes in the peripheral T cell pool, in the predominant phenotype, cytokine production profiles, signalling function and in replicative ability following stimulus with antigen, mitogens or anti-CD3 antibody. These changes in the properties of peripheral T cells are thought to be causally linked to an age-associated involution in the thymus. Our analysis reveals that thymic involution is due to a change in the thymic microenvironment linked to a reduction in the level of available interleukin 7. Treatment with interleukin 7 leads to a reversal of thymic atrophy with increased thymopoiesis. This provides the potential to reverse the immune dysfunction seen in the peripheral T cell pool by replacing old cells with new output generated in the thymus. Problems to overcome in order for such an experimental therapy to be successful require careful analysis in order to provide an optimal strategy to ensure that new T cell emigrants from the thymus have a broad range of specificities and are able to enter the peripheral T cell pool.

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Age-related decrease of somatostatin receptor number in the normal human thymus

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.279.4.e791 ◽

2000 ◽

Vol 279 (4) ◽

pp. E791-E798 ◽

Cited By ~ 17

Author(s):

Diego Ferone ◽

Rosario Pivonello ◽

P. Martin Van Hagen ◽

Marlijn Waaijers ◽

Joke Zuijderwijk ◽

...

Keyword(s):

Structural Changes ◽

Somatostatin Receptor ◽

Thymic Epithelial Cells ◽

Thymic Involution ◽

Human Thymus ◽

Age Related ◽

Tissue Homogenates ◽

Normal Human ◽

Receptor Number ◽

Age Range

The thymus exhibits a pattern of aging oriented toward a physiological involution. The structural changes start with a steady decrease of thymocytes, whereas no major variations occur in the number of thymic epithelial cells (TEC). The data concerning the role of hormones and neuropeptides in thymic involution are equivocal. We recently demonstrated the presence of somatostatin (SS) and three different SS receptor (SSR) subtypes in the human thymus. TEC selectively expressed SSR subtype 1 (sst1) and sst2a. In the present study we investigated whether SSR number is age related in the thymus. Binding of the sst2-preferring ligand125I-Tyr3-octreotide was evaluated in a large series of normal human thymuses of different age by SSR autoradiography and ligand binding on tissue homogenates. The score at autoradiography and the number of SSR at membrane homogenate binding (Bmax) were inversely correlated with the thymus age ( r = −0.84, P < 0.001; r = −0.82, P < 0.001, respectively). The autoradiographic score was positively correlated with the Bmaxvalues ( r = 0.74, P < 0.001). Because the TEC number in the age range considered remains unchanged, the decrease of octreotide binding sites might be due to a reduction of sst2areceptor number on TEC. The age-related expression of a receptor involved mainly in controlling secretive processes is in line with the evidence that the major changes occurring in TEC with aging are related to their capabilities in producing thymic hormones. In conclusion, SS and SSR might play a role in the involution of the human thymus. These findings underline the links between the neuroendocrine and immune systems and support the concept that neuropeptides participate in development of cellular immunity in humans.

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Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1519118112 ◽

2015 ◽

Vol 112 (44) ◽

pp. E6020-E6027 ◽

Cited By ~ 22

Author(s):

Martijn H. Brugman ◽

Anna-Sophia Wiekmeijer ◽

Marja van Eggermond ◽

Ingrid Wolvers-Tettero ◽

Anton W. Langerak ◽

...

Keyword(s):

T Cell ◽

T Cell Development ◽

Xenograft Model ◽

Subsequent Development ◽

Cell Receptor ◽

Cell Development ◽

Cell Repertoire ◽

Hematopoietic Stem ◽

Human T Cell ◽

Hsc Transplantation

The fate and numbers of hematopoietic stem cells (HSC) and their progeny that seed the thymus constitute a fundamental question with important clinical implications. HSC transplantation is often complicated by limited T-cell reconstitution, especially when HSC from umbilical cord blood are used. Attempts to improve immune reconstitution have until now been unsuccessful, underscoring the need for better insight into thymic reconstitution. Here we made use of the NOD-SCID-IL-2Rγ−/− xenograft model and lentiviral cellular barcoding of human HSCs to study T-cell development in the thymus at a clonal level. Barcoded HSCs showed robust (>80% human chimerism) and reproducible myeloid and lymphoid engraftment, with T cells arising 12 wk after transplantation. A very limited number of HSC clones (<10) repopulated the xenografted thymus, with further restriction of the number of clones during subsequent development. Nevertheless, T-cell receptor rearrangements were polyclonal and showed a diverse repertoire, demonstrating that a multitude of T-lymphocyte clones can develop from a single HSC clone. Our data imply that intrathymic clonal fitness is important during T-cell development. As a consequence, immune incompetence after HSC transplantation is not related to the transplantation of limited numbers of HSC but to intrathymic events.

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