Expression of 4-1BB and 4-1BBL in thymocytes during thymus regeneration

Kim, Youngmi; Kim, Hye Kyung; Kim, Hyo Jin; Lee, Hae Young; Ju, Seong‐A; Choi, Beom K.; Kwon, Byoung S.; Kim, Bong-Seon; Kim, Jae-Bong; Lim, Yooseong; Yoon, Sik

doi:10.3858/emm.2009.41.12.095

Cited by 11 publications

(9 citation statements)

References 55 publications

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“…The mice were allowed to acclimate to their environment for 1 week, and were used at 8-10-weeks-of-age. Because cyclophosphamide, a DNA alkylating agent commonly used in chemotherapy, is a long-established method for investigating thymic regeneration [ 23 - 28 ], the animals were given a single intraperitoneal dose of cyclophosphamide (400 mg/kg body weight, Sigma, St. Louis, MO, USA) in normal saline and were killed in groups of four or more at 3, 7, and 14 days after injection. Mice given the same volume of normal saline were used as controls.…”

Section: Methodsmentioning

confidence: 99%

Characterization of the expression of cytokeratins 5, 8, and 14 in mouse thymic epithelial cells during thymus regeneration following acute thymic involution

et al. 2011

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The thymus is a central lymphoid organ for T cell development. Thymic epithelial cells (TECs) constitute a major component of the thymic stroma, which provides a specialized microenvironment for survival, proliferation, and differentiation of immature T cells. In this study, subsets of TECs were examined immunohistochemically to investigate their cytokeratin (CK) expression patterns during thymus regeneration following thymic involution induced by cyclophosphamide treatment. The results demonstrated that both normal and regenerating mouse thymuses showed a similar CK expression pattern. The major medullary TECs (mTEC) subset, which is stellate in appearance, exhibited CK5 and CK14 staining, and the minor mTEC subset, which is globular in appearance, exhibited CK8 staining, whereas the vast majority of cortical TECs (cTECs) expressed CK8 during thymus regeneration. Remarkably, the levels of CK5 and CK14 expression were enhanced in mTECs, and CK8 expression was upregulated in cTECs during mouse thymus regeneration after cyclophosphamide-induced acute thymic involution. Of special interest, a relatively high number of CK5+CK8+ TEC progenitors occurred in the thymic cortex during thymus regeneration. Taken together, these findings shed more light on the role of CK5, CK8, and CK14 in the physiology of TECs during mouse thymus regeneration, and on the characterization of TEC progenitors for restoration of the epithelial network and for concomitant regeneration of the adult thymus.

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Section: Methodsmentioning

confidence: 99%

Characterization of the expression of cytokeratins 5, 8, and 14 in mouse thymic epithelial cells during thymus regeneration following acute thymic involution

et al. 2011

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“…4-1BB is expressed on a multitude of cells of the hematopoietic lineage ( 13 ). While 4-1BB is widely known to be transiently upregulated on CD8 T cells following activation ( 14 – 18 ), 4-1BB can also be expressed on activated CD4 helper T cells ( 17 , 19 , 20 ), B cells ( 21 , 22 ), regulatory T cells ( 23 ), natural killer (NK) cells ( 24 – 26 ), natural killer T (NKT) cells ( 27 ), gamma-delta T cells ( 28 ), dendritic cells ( 29 , 30 ), mast cells ( 31 ), osteoclasts ( 32 , 33 ), thymocytes ( 34 ), early myeloid progenitor cells ( 35 , 36 ), and activated endothelium ( 37 – 40 ). Human neural cells also express 4-1BB, including neurons, astroglia, and microglia in the brain ( 41 ).…”

Section: The Role Of 4-1bb In the Immune Responsementioning

confidence: 99%

4-1BB Agonists: Multi-Potent Potentiators of Tumor Immunity

2015

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Immunotherapy is a rapidly expanding field of oncology aimed at targeting, not the tumor itself, but the immune system combating the cancerous lesion. Of the many approaches currently under study to boost anti-tumor immune responses; modulation of immune co-receptors on lymphocytes in the tumor microenvironment has thus far proven to be the most effective. Antibody blockade of the T cell co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) has become the first FDA approved immune checkpoint blockade; however, tumor infiltrating lymphocytes express a diverse array of additional stimulatory and inhibitory co-receptors, which can be targeted to boost tumor immunity. Among these, the co-stimulatory receptor 4-1BB (CD137/TNFSF9) possesses an unequaled capacity for both activation and pro-inflammatory polarization of anti-tumor lymphocytes. While functional studies of 4-1BB have focused on its prominent role in augmenting cytotoxic CD8 T cells, 4-1BB can also modulate the activity of CD4 T cells, B cells, natural killer cells, monocytes, macrophages, and dendritic cells. 4-1BB’s expression on both T cells and antigen presenting cells, coupled with its capacity to promote survival, expansion, and enhanced effector function of activated T cells, has made it an alluring target for tumor immunotherapy. In contrast to immune checkpoint blocking antibodies, 4-1BB agonists can both potentiate anti-tumor and anti-viral immunity, while at the same time ameliorating autoimmune disease. Despite this, 4-1BB agonists can trigger high grade liver inflammation which has slowed their clinical development. In this review, we discuss how the underlying immunobiology of 4-1BB activation suggests the potential for therapeutically synergistic combination strategies in which immune adverse events can be minimized.

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“…The strategies developed thus far; such as the use of sex steroid ablation (Greenstein et al, ; Windmill and Lee, ), keratinocyte growth factor (Min et al, ; Alpdogan et al, ; Rossi et al, ), IL‐7 (Bolotin et al, ; Mackall et al, ; Aspinall et al, ; Goldberg et al, ), and in vitro‐generated progenitor T‐cells (Awong et al, ), could effectively restore the thymic architecture and cellularity in animal models. In addition, in previous studies, we showed that other factors such as nerve growth factor (Lee et al, , ), 4‐1BBL (Kim et al, ), receptor activator of nuclear factor‐κB ligand (Lee et al, , ), and TrkA neurotrophin receptor (Yoon et al, ) appear to be important in thymic regeneration. We used stem cell‐based gene therapy to enhance T‐cell reconstitution, and demonstrated the stimulatory effect of HGF‐hATMSCs on thymic regeneration for promoting TEC proliferation and IL‐7 expression in vitro, as well as to increase of the thymus size and the number of thymocytes in a rat model of CY‐induced acute thymus involution.…”

Section: Discussionmentioning

confidence: 65%

Stimulatory effect of HGF‐overexpressing adipose tissue‐derived mesenchymal stem cells on thymus regeneration in a rat thymus involution model

Jung

Han

Kim

et al. 2014

Cell Biology International

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The thymus is the central lymphoid organ providing a unique and essential microenvironment for T-cell precursor development into mature functionally competent T-lymphocytes. Thus, it is important to develop the strategies for enhancing thymic regeneration from involution induced by a variety of clinical treatments and conditions. Hepatocyte growth factor (HGF) promotes proliferation in a variety of cell types. We have used stem cell-based HGF gene therapy to enhance regeneration from acute thymic involution. HGF-overexpressing human adipose tissue-derived mesenchymal stem cells (HGF-hATMSCs) were generated by liposomal transfection with the pMEX expression vector, constructed by inserting the HGF gene. Significantly increased HGF expression in these cells was confirmed by reverse transcription-polymerase chain reaction and an enzyme-linked immunosorbent assay. HGF produced by HGF-hATMSCs enhanced the proliferation of a mouse thymic epithelial cell line and the expression of interleukin-7 in vitro. We also examined the effect of HGF-hATMSCs on thymic regeneration in rats with acute thymic involution. Significant increases in thymus size and weight, as well as the number of thymocytes (especially, early thymocyte progenitors), were seen in the HGF-hATMSCs-treated rats compared to saline-treated control animals. A stimulatory effect of HGF-hATMSCs on thymic regeneration has therefore been shown, highlighting the clinical value of HGF-hATMSCs for treating thymic involution.

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Expression of 4-1BB and 4-1BBL in thymocytes during thymus regeneration

Cited by 11 publications

References 55 publications

Characterization of the expression of cytokeratins 5, 8, and 14 in mouse thymic epithelial cells during thymus regeneration following acute thymic involution

Characterization of the expression of cytokeratins 5, 8, and 14 in mouse thymic epithelial cells during thymus regeneration following acute thymic involution

4-1BB Agonists: Multi-Potent Potentiators of Tumor Immunity

Stimulatory effect of HGF‐overexpressing adipose tissue‐derived mesenchymal stem cells on thymus regeneration in a rat thymus involution model

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