Dynamic regulation of IL-7 receptor expression is required for normal thymopoiesis

Abstract Interleukin-7 receptor (IL-7R) levels are tightly controlled during ontogeny: high on double-negative (DN) cells, absent on double-positive (DP) cells, and high once again on thymocytes undergoing positive selection. To determine if loss of IL-7–mediated survival signals in DP cells is necessary for normal antigen-specific selection, we created T-lineage–specific IL-7R α chain (IL-7Rα) transgenic (Tg) mice in which IL-7R is expressed throughout ontogeny. There was no effect of the IL-7Rα Tg on negative selection. Surprisingly, however, although the thymi of IL-7Rα Tg mice were comparable at birth, there was a decrease in thymocyte number as the mice aged. This was found to be due to competition between DN and IL-7R–expressing DP cells for endogenous IL-7, which resulted in decreased levels of Bcl-2 in DN cells, increased DN apoptosis, and decreased DN cell number. Therefore, the down-regulation of IL-7R on DP cells is an “altruistic” act required for maintaining an adequate supply of local IL-7 for DN cells.

Download Full-text

A novel single step double positive double negative selection strategy for β-globin gene replacement

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2006.04.060 ◽

2006 ◽

Vol 345 (1) ◽

pp. 14-20 ◽

Cited By ~ 2

Author(s):

H. Khanahmad ◽

M.R. Noori Daloii ◽

M.A. Shokrgozar ◽

K. Azadmanesh ◽

A.R. Niavarani ◽

...

Keyword(s):

Negative Selection ◽

Globin Gene ◽

Gene Replacement ◽

Single Step ◽

Selection Strategy ◽

Double Negative ◽

Double Positive

Download Full-text

Cell competition, the kinetics of thymopoiesis and thymus cellularity are regulated by double negative 2 to 3 early thymocytes

10.1101/2019.12.21.885673 ◽

2019 ◽

Cited By ~ 1

Author(s):

Camila V. Ramos ◽

Luna Ballesteros-Arias ◽

Joana G. Silva ◽

Rafael A. Paiva ◽

Marta F. Nogueira ◽

...

Keyword(s):

Feedback Loop ◽

Cycle Duration ◽

Double Negative ◽

Cell Competition ◽

Double Positive ◽

Homeostatic Process ◽

Interleukin 7 ◽

The Impact ◽

Kinetics Of ◽

Fine Tune

SUMMARYCell competition in the thymus is a homeostatic process that drives turnover. If the process is impaired, thymopoiesis can be autonomously maintained for several weeks, but this causes leukemia. We aimed to understand the impact of cell competition on thymopoiesis, identify the cells involved and determine how the process is regulated. Using thymus transplantation experiments we found that cell competition occurs within the double negative 2 (DN2) and 3 early (DN3e) thymocytes and inhibits thymus autonomy. Furthermore, the expansion of DN2b is regulated by a negative feedback loop imposed by double positive thymocytes and determines the kinetics of thymopoiesis. This feedback loop impacts on cell cycle duration of DN2b, in a response controlled by interleukin 7 availability. Altogether, we show that thymocytes do not merely follow a pre-determined path if provided with the correct signals. Instead, thymopoiesis dynamically integrates cell autonomous and non-cell autonomous aspects that fine-tune normal thymus function.

Download Full-text

A novel mouse thymocyte antigen (F3Ag): down-regulation during the CD4+CD8+ double-positive stage indicates positive selection

International Immunology ◽

10.1093/intimm/8.1.101 ◽

1996 ◽

Vol 8 (1) ◽

pp. 101-113 ◽

Cited By ~ 8

Author(s):

Thomas Barthlott ◽

Alexandre J. Potocnik ◽

Hubertus Kohler ◽

Rita Carsetti ◽

Hanspeter Pircher ◽

...

Keyword(s):

Positive Selection ◽

Double Positive ◽

Down Regulation ◽

Mouse Thymocyte

Download Full-text

Vitamin D decreasesin vitroglucocorticoid sensitivity via down regulation of glucocorticoid receptor expression

Endocrine Abstracts ◽

10.1530/endoabs.37.oc5.2 ◽

2015 ◽

Author(s):

Narjes Nasiri Ansari ◽

Eliana Spilioti ◽

Vasiliki Kalotychou ◽

Geena Dalagiorgou ◽

Paraskevi Moutsatsou ◽

...

Keyword(s):

Vitamin D ◽

Glucocorticoid Receptor ◽

Receptor Expression ◽

Down Regulation

Download Full-text

Faculty Opinions recommendation of Unequal contribution of Akt isoforms in the double-negative to double-positive thymocyte transition.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1082856.535797 ◽

2007 ◽

Author(s):

Mark Boothby

Keyword(s):

Double Negative ◽

Double Positive ◽

Akt Isoforms ◽

Double Positive Thymocyte

Download Full-text

Lower Monocyte Interleukin-7 Receptor Expression Impairs Anti-Mycobacterial Effector Functions in Tuberculosis Patients

SSRN Electronic Journal ◽

10.2139/ssrn.3710619 ◽

2020 ◽

Author(s):

Ernest Adankwah ◽

Jean Harelimana ◽

Difery Minadzi ◽

Wilfred Aniagyei ◽

Mohammed K. Abass ◽

...

Keyword(s):

Receptor Expression ◽

Tuberculosis Patients ◽

Effector Functions ◽

Interleukin 7

Download Full-text

Interleukin 7 Transgenic Mice Develop Chronic Colitis with Decreased Interleukin 7 Protein Accumulation in the Colonic Mucosa

Journal of Experimental Medicine ◽

10.1084/jem.187.3.389 ◽

1998 ◽

Vol 187 (3) ◽

pp. 389-402 ◽

Cited By ~ 152

Author(s):

Mamoru Watanabe ◽

Yoshitaka Ueno ◽

Tomoharu Yajima ◽

Susumu Okamoto ◽

Tatsuhiko Hayashi ◽

...

Keyword(s):

T Cells ◽

Epithelial Cells ◽

Transgenic Mice ◽

Chronic Inflammation ◽

Colonic Mucosa ◽

Flow Cytometric Analysis ◽

Receptor Expression ◽

Protein Accumulation ◽

Chronic Colitis ◽

Interleukin 7

We have demonstrated that intestinal epithelial cells produce interleukin 7 (IL-7), and IL-7 serves as a potent regulatory factor for proliferation of intestinal mucosal lymphocytes expressing functional IL-7 receptor. To clarify the mechanism by which locally produced IL-7 regulates the mucosal lymphocytes, we investigated IL-7 transgenic mice. Here we report that transgenic mice expressing murine IL-7 cDNA driver by the SRα promoter developed chronic colitis in concert with the expression of SRα/IL-7 transgene in the colonic mucosa. IL-7 transgenic but not littermate mice developed chronic colitis at 4–12 wk of age, with histopathological similarity to ulcerative colitis in humans. Southern blot hybridization and competitive PCR demonstrated that the expression of IL-7 messenger RNA was increased in the colonic mucosal lymphocytes but not in the colonic epithelial cells. IL-7 protein accumulation was decreased in the goblet cell–depleted colonic epithelium in the transgenic mice. Immunohistochemical and cytokine production analysis showed that lymphoid infiltrates in the lamina propria were dominated by T helper cell type 1 CD4+ T cells. Flow cytometric analysis demonstrated that CD4+ intraepithelial T cells were increased, but T cell receptor γ/δ T cells and CD8α/α cells were not increased in the area of chronic inflammation. Increased IL-7 receptor expression in mucosal lymphocytes was demonstrated in the transgenic mice. These findings suggest that chronic inflammation in the colonic mucosa may be mediated by dysregulation of colonic epithelial cell–derived IL-7, and this murine model of chronic colitis may contribute to the understanding of the pathogenesis of human inflammatory bowel disease.

Download Full-text