Altered thymic epithelial cells may be decisive for Moloney virus-induced lymphoma development

Infection of newborn mice with Moloney leukemia virus (M-MuLV) causes a T-cell differentiation block in the thymic cortex accompanied by proliferation and accumulation of prethymic lymphoblasts in the thymus and subsequent spreading of these cells to generate systemic lymphoma. Current evidence shows that thymic reticular epithelial cells (REC) provide a microenvironment necessary for the maturation of prethymic lymphoblasts to mature T-lymphocytes by secretion of various thymic factors. A change in that environment due to infection of REC by virus could be decisive for the failure of lymphoblasts to mature and thus contribute to lymphoma development.We have studied the morphology and distribution of the major thymic cell populations at different stages of tumorigenesis in Balb/c mice infected when newborn with 0.2ml M-MuLV suspension, 6.8 log FFU/ml. Thymic tissue taken at 1-2 weekly intervals up to tumor development was processed for light and electron microscopy, using glutaraldehyde-OsO4fixation and Epon-Araldite embedding.

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RB Controls Size, Cellularity, and T Cell Output of the Mouse Thymus

Blood ◽

10.1182/blood.v120.21.835.835 ◽

2012 ◽

Vol 120 (21) ◽

pp. 835-835

Author(s):

Phillip M. Garfin ◽

Patrick Viatour ◽

Dullei Min ◽

Jerrod Bryson ◽

Kenneth I. Weinberg ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Epithelial Cells ◽

Conflicts Of Interest ◽

Thymic Epithelial Cells ◽

Main Function ◽

Thymic Involution ◽

Regulatory Relationship ◽

Thymic Tissue ◽

Rb Pathway

Abstract Abstract 835 The establishment of the thymic microenvironment early in life is crucial for the production functional T cells. Conversely, thymic involution results in a decreased T cell output. Thymic involution has important health implications especially following bone marrow transplant. Our objective is to determine molecular and cellular mechanisms that will allow for regeneration of involuted thymic tissue, restore production of naïve T cells, and improve immune function while improving our understanding of immunobiology. In this pursuit, we have focused on the Retinoblastoma family of tumor suppressor proteins. The main function of the RB pathway is to restrict passage through the G1/S transition of the cell cycle. RB and its two family members, p107 and p130, mediate the action of a broad range of cellular signals to control the proliferation, survival, and differentiation status of a large number of mammalian cell types. We found that inactivation of the RB pathway in the thymus by early deletion of RB family genes prevents thymic involution, promotes expansion of functional thymic epithelial cells (TECs), and increases thymic T cell output. Moreover, we have identified a direct regulatory relationship between RB and the Foxn1 transcription factor Via E2F transcription factors, where RB/E2F complexes directly repress the Foxn1 promoter, thereby promoting involution. Thus, the RB family is a critical mediator of extra- and intra-cellular signals to regulate thymic epithelial cells and thymus function, and decreasing RB pathway function may promote regeneration of the involuted thymus and restoration of naïve T cell production in patients. Disclosures: No relevant conflicts of interest to declare.

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Characterization of an antigenic determinant preferentially expressed by type I epithelial cells in the murine thymus.

Journal of Histochemistry & Cytochemistry ◽

10.1177/40.5.1374092 ◽

1992 ◽

Vol 40 (5) ◽

pp. 651-664 ◽

Cited By ~ 37

Author(s):

A Farr ◽

A Nelson ◽

S Hosier

Keyword(s):

Epithelial Cells ◽

Cell Lines ◽

Stromal Cell ◽

Thymic Epithelial Cells ◽

Type I ◽

Thymic Tissue ◽

Reducing Conditions ◽

Thymus Tissue ◽

Vascular Structures ◽

Thymic Stromal Cell

A hamster monoclonal antibody (MAb), designated 8.1.1, was raised against murine thymic stromal cell lines and was found to react with cell surface molecules expressed by a morphologically distinct population of epithelial cells of the murine thymus comprising the subcapsular environment, cells investing vascular structures throughout the thymus, and some of the cellular elements in the medulla. The epithelial nature of the labeled cells was confirmed with immunoelectron microscopy. Reactivity with MAb 8.1.1 was associated with thymic epithelial cells in contact with basal laminae. Ontological studies of thymic tissue demonstrated that the epitope recognized by this MAb was expressed before Day 14 of gestation, although the restricted subcapsular and medullar expression of 8.1.1 was not apparent until sometime after birth. MAb 8.1.1 also reacted with a number of extra-thymic tissues, including lamina propria of gut, glomeruli and tubules in the kidney, mesothelia covering a number of organs, and the dermis and epidermis of skin. Within the epidermis, reactivity of MAb 8.1.1 was largely restricted to basal epithelial cells. Immunochemical analysis of 8.1.1 reactivity with detergent-soluble extracts of thymic stromal cell lines and thymus tissue indicated that detergent-soluble extracts of thymic stromal cell lines and thymus tissue indicated that the epitope recognized by this MAb was associated with a glycoprotein bearing terminal N-acetylglucosamine residues and possessing an Mr of approximately 36-38 KD under reducing or non-reducing conditions.

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Monoclonal antibody against human T cell leukemia virus p19 defines a human thymic epithelial antigen acquired during ontogeny.

Journal of Experimental Medicine ◽

10.1084/jem.157.3.907 ◽

1983 ◽

Vol 157 (3) ◽

pp. 907-920 ◽

Cited By ~ 71

Author(s):

B F Haynes ◽

M Robert-Guroff ◽

R S Metzgar ◽

G Franchini ◽

V S Kalyanaraman ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Epithelial Cells ◽

Leukemia Virus ◽

Thymic Epithelial Cells ◽

Cortical Region ◽

Cell Leukemia ◽

Thymic Epithelium ◽

Human T Cell ◽

T Cell Leukemia Virus

Using monoclonal antibody 12/1-2 against a 19,000-dalton human T cell leukemia virus (HTLV) protein (anti-p19), previously demonstrated to be reactive with HTLV-infected human cells, but not in numerous other uninfected cells, we found a reactive antigen to be expressed on the neuroendocrine component of human thymic epithelial cells but not on any other normal epithelial or neuroendocrine human tissues. Moreover, this reactive antigen is acquired on neuroendocrine thymic epithelium during thymic ontogeny--first appearing on fetal thymic epithelial cells between 8 and 15 wk gestation. While only a portion of thymic epithelial cells in the subcapsular cortical region of 15- and 24-wk fetal thymuses contained anti-p19+ epithelial cells, the entire subcapsular cortical region of newborn thymus epithelium was anti-p19+. By age 3 yr, normal subjects' entire subcapsular cortical and medullary thymic epithelium was anti-p19+. Using antibody against HTLV core protein, p24, and c-DNA probes for HTLV DNA, neither HTLV-specific p24 protein nor proviral DNA could be demonstrated in anti-p19+ thymic epithelial tissue. However, thymic epithelial extracts, disrupted HTLV extracts, as well as purified HTLV p19 antigen all inhibited the binding of anti-p19 antibody to thymic epithelium. Thus, anti-p19 may recognize a determinant on an HTLV-encoded 19,000-dalton structural protein that is shared by human thymic epithelium. Alternatively, anti-p19 defines a host encoded protein that is selectively expressed by normal thymic epithelium, and is induced to be expressed in HTLV-infected malignant T cells.

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PDGFRα-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches

Blood ◽

10.1182/blood-2006-05-023143 ◽

2006 ◽

Vol 109 (3) ◽

pp. 954-960 ◽

Cited By ~ 60

Author(s):

William E. Jenkinson ◽

Simona W. Rossi ◽

Sonia M. Parnell ◽

Eric J. Jenkinson ◽

Graham Anderson

Keyword(s):

T Cells ◽

T Cell ◽

Epithelial Cells ◽

Growth Factor Receptor ◽

Thymic Epithelial Cells ◽

Thymic Tissue ◽

Mhc Molecules ◽

Histocompatibility Complex ◽

Medullary Epithelial Cells ◽

Selection Of

Abstract The thymus provides a specialized site for the production of T cells capable of recognizing foreign antigens in the context of self–major histocompatibility complex (MHC) molecules. During development, the thymus arises from an epithelial rudiment containing bipotent progenitors that differentiate into distinct cortical and medullary epithelial cells to regulate the maturation and selection of self-tolerant CD4+ and CD8+ T cells. In addition to their differentiation, thymic epithelial cells undergo cellular expansion to ensure that sufficient intrathymic cellular niches are available to support the large number of immature thymocytes required to form a self-tolerant T-cell pool. Thus, intrathymic T-cell production is intimately linked to the formation and availability of niches within thymic microenvironments. Here, we show the increase in intrathymic niches caused by the proliferation of the epithelium in the developing thymus is temporally regulated, and correlates with the presence of a population of fetal thymic mesenchyme defined by platelet-derived growth factor receptor α (PDGFRα) expression. Depletion of PDGFRα+ mesenchyme from embryonic thymi prior to their transplantation to ectopic sites results in the formation of functional yet hypoplastic thymic tissue. In summary, we highlight a specialized role for PDGFRα+ fetal mesenchyme in the thymus by determining availability of thymic niches through the regulation of thymic epithelial proliferation.

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In Vitro Characterization of Somatostatin Receptors in the Human Thymus and Effects of Somatostatin and Octreotide on Cultured Thymic Epithelial Cells

Endocrinology ◽

10.1210/endo.140.1.6398 ◽

1999 ◽

Vol 140 (1) ◽

pp. 373-380 ◽

Cited By ~ 38

Author(s):

Diego Ferone ◽

P. Martin van Hagen ◽

Peter M. van Koetsveld ◽

Joke Zuijderwijk ◽

Diana M. Mooy ◽

...

Keyword(s):

Epithelial Cells ◽

Thymic Epithelial Cells ◽

Rt Pcr ◽

Binding Studies ◽

Thymic Tissue ◽

High Affinity ◽

Human Thymus ◽

Normal Human

Abstract Somatostatin (SS) and its analogs exert inhibitory effects on secretive and proliferative processes of various cells via high affinity SS receptors (SS-R). SS analogs bind with different affinity to the five cloned SS-R subtypes. Octreotide, an octapeptide SS analog, binds with high affinity to the SS-R subtype 2 (sst2). SS-R have been demonstrated in vivo and in vitro on cells from endocrine and immune systems. Among the lymphatic tissues, the thymus has been shown to contain the highest amount of SS, suggesting a local functional role of the peptide. We investigated the SS distribution and SS-R expression pattern in the normal human thymus using autoradiography, membrane homogenate binding studies, and RT-PCR. In addition, the effect of SS and octreotide on growth of cultured thymic epithelial cells (TEC) was studied. By autoradiography, binding of[ 125I-Tyr0]-SS-28 and[ 125I-Tyr3]-octreotide was detected in all seven thymuses studied. Specific[ 125I-Tyr3]-octreotide binding was shown on membrane preparations from thymuses, while not from cultured thymocytes. RT-PCR showed the expression of sst1, sst2A and sst3 messenger RNA (mRNA) in the thymic tissue, whereas sst1 and sst2A mRNAs were found in isolated TEC. SS mRNA was present in thymic tissue and in isolated TEC. SS and octreotide significantly inhibited 3H-thymidine incorporation in 3 of 3 and 6 of 6 TEC cultures, respectively. The percent inhibition ranged from 38.8 to 66.8% for SS and from 19.1 to 59.5% for octreotide. In conclusion, SS mRNA and sst1, sst2A, and sst3 mRNAs are expressed in the normal human thymus. Cultured TEC selectively express sst1 and sst2A mRNA and respond in vitro to SS and octreotide administration with an inhibition of cell proliferation. These data suggest a paracrine/autocrine role of SS and its receptors in the regulation of cell growth in thymic microenvironment.

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Induction of intestinal lesions in nu/nu mice induced by transfer of lymphocytes from syngeneic mice infected with murine retrovirus

Gut ◽

10.1136/gut.41.2.221 ◽

1997 ◽

Vol 41 (2) ◽

pp. 221-228 ◽

Cited By ~ 7

Author(s):

K Suzuki ◽

T Narita ◽

R Yui ◽

K Ohtsuka ◽

S Inada ◽

...

Keyword(s):

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Histopathological Examination ◽

Leukemia Virus ◽

Light And Electron Microscopy ◽

Experimental System ◽

Intestinal Epithelial ◽

Virus Particles ◽

Intestinal Lesions ◽

Anal Bleeding

Background—Murine leukemia virus, LP-BM5, induces severe immunodeficiency with abnormal lymphoproliferation in susceptible C57BL/6 mice. In a previous study, it was shown that a Sjögren’s syndrome-like systemic exocrinopathy is induced in the virus infected mice.Aims—To examine lymphocyte functions of the virus infected mice.Methods—Four-week old mice were inoculated with the virus and their spleen cells were transferred into syngeneic nu/nu mice. Their organs were examined by light and electron microscopy. Phenotypes of the colon infiltrating cells were examined by flow cytometry.Results—All nu/nu recipients had died by six weeks after cell transfer, showing runting disease like cachexia with diarrhoea and anal bleeding. Histopathological examination revealed that systemic exocrinopathy was adoptively transferable and that the colon became thickened due to mononuclear cell infiltration into the mucosal and submucosal layer with hyperplasia of intestinal epithelial cells. No virus particles were found in the colon. Flow cytometric analyses revealed that most of the infiltrating CD4+ T cells showed CD45RBlow. No intestinal lesions were observed in the virus infected mice nor in nu/nu mice inoculated with normal lymphocytes.Conclusion—Lymphocytes of the virus infected mice induced colitis and hyperplasia of intestinal epithelial cells as well as systemic exocrinopathy in nu/nu mice. Our experimental system may give some insight into intestinal lesions associated with virus infection.

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Aberrant Type C Virus Production in a Cell Line Derived from Balb/3T3

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100094693 ◽

1972 ◽

Vol 30 ◽

pp. 286-287

Author(s):

N. Savage ◽

A. Hackett

Keyword(s):

Electron Microscopy ◽

Cell Line ◽

Leukemia Virus ◽

Morphological Characteristics ◽

Virus Production ◽

Oncogenic Viruses ◽

Endogenous Virus ◽

Virus Particles ◽

Moloney Leukemia Virus ◽

A Cell

A cell line, UC1-B, which was derived from Balb/3T3 cells, maintains the same morphological characteristics of the non-transformed parental culture, and shows no evidence of spontaneous virus production. Survey by electron microscopy shows that the cell line consists of spindle-shaped cells with no unusual features and no endogenous virus particles.UC1-B cells respond to Moloney leukemia virus (MLV) infection by a change in morphology and growth pattern which is typical of cells transformed by sarcoma virus. Electron microscopy shows that the cells are now variable in shape (rounded, rhomboid, and spindle), and each cell type has some microvilli. Virtually all (90%) of the cells show virus particles developing at the cell surface and within the cytoplasm. Maturing viruses, typical of the oncogenic viruses, are found along with atypical tubular forms in the same cell.

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