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Title: Abdominal {gamma}-Radiation Induces an Accumulation of Function-Impaired Regulatory T Cells in the Small Intestine

Abstract

Purpose: To assess the frequency and the functional characteristics of one major component of immune tolerance, the CD4{sup +}FoxP3{sup +} regulatory T cells (Tregs) in a mouse model of abdominal irradiation. Methods and Materials: Mice were exposed to a single abdominal dose of {gamma}-radiation (10 Gy). We evaluated small intestine Treg infiltration by Foxp3 immunostaining and the functional suppressive activity of Tregs isolated from mesenteric lymph nodes. Results: Foxp3 immunostaining showed that radiation induced a long-term infiltration of the intestine by Tregs (levels 5.5 times greater than in controls). Co-culture of Tregs from mesenteric lymph nodes with CD4{sup +} effector cells showed that the Tregs had lost their suppressive function. This loss was associated with a significant decrease in the levels of Foxp3, TGF-{beta}, and CTLA-4 mRNA, all required for optimal Treg function. At Day 90 after irradiation, Tregs regained their suppressive activity as forkhead box P3 (Foxp3), transforming growth factor beta (TGF-{beta}), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression returned to normal. Analysis of the secretory function of mesenteric lymph node Tregs, activated in vitro with anti-CD3/anti-CD28 Abs, showed that this dysfunction was independent of a defect in interleukin-10 secretion. Conclusion: Radiation caused a long-term accumulation of function-impaired Foxp3{supmore » +}CD4{sup +} Tregs in the intestine. Our study provides new insights into how radiation affects the immune tolerance in peripheral tissues.« less

Authors:
; ;  [1];  [1]
  1. Institut de Radioprotection et de Surete Nucleaire, Direction de la Radioprotection de l'Homme, B.P. no. 17, Fontenay-aux-Roses (France)
Publication Date:
OSTI Identifier:
21587575
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 80; Journal Issue: 3; Other Information: DOI: 10.1016/j.ijrobp.2010.12.041; PII: S0360-3016(11)00029-0; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; GAMMA RADIATION; IMMUNITY; IRRADIATION; LYMPH NODES; LYMPHOCYTES; RADIATION DOSES; SMALL INTESTINE; ANIMAL CELLS; BIOLOGICAL MATERIALS; BLOOD; BLOOD CELLS; BODY; BODY FLUIDS; CONNECTIVE TISSUE CELLS; DIGESTIVE SYSTEM; DOSES; ELECTROMAGNETIC RADIATION; GASTROINTESTINAL TRACT; INTESTINES; IONIZING RADIATIONS; LEUKOCYTES; LYMPHATIC SYSTEM; MATERIALS; ORGANS; RADIATIONS; SOMATIC CELLS

Citation Formats

Billiard, Fabienne, Buard, Valerie, Benderitter, Marc, and Linard, Christine, E-mail: christine.linard@irsn.fr. Abdominal {gamma}-Radiation Induces an Accumulation of Function-Impaired Regulatory T Cells in the Small Intestine. United States: N. p., 2011. Web. doi:10.1016/j.ijrobp.2010.12.041.
Billiard, Fabienne, Buard, Valerie, Benderitter, Marc, & Linard, Christine, E-mail: christine.linard@irsn.fr. Abdominal {gamma}-Radiation Induces an Accumulation of Function-Impaired Regulatory T Cells in the Small Intestine. United States. doi:10.1016/j.ijrobp.2010.12.041.
Billiard, Fabienne, Buard, Valerie, Benderitter, Marc, and Linard, Christine, E-mail: christine.linard@irsn.fr. 2011. "Abdominal {gamma}-Radiation Induces an Accumulation of Function-Impaired Regulatory T Cells in the Small Intestine". United States. doi:10.1016/j.ijrobp.2010.12.041.
@article{osti_21587575,
title = {Abdominal {gamma}-Radiation Induces an Accumulation of Function-Impaired Regulatory T Cells in the Small Intestine},
author = {Billiard, Fabienne and Buard, Valerie and Benderitter, Marc and Linard, Christine, E-mail: christine.linard@irsn.fr},
abstractNote = {Purpose: To assess the frequency and the functional characteristics of one major component of immune tolerance, the CD4{sup +}FoxP3{sup +} regulatory T cells (Tregs) in a mouse model of abdominal irradiation. Methods and Materials: Mice were exposed to a single abdominal dose of {gamma}-radiation (10 Gy). We evaluated small intestine Treg infiltration by Foxp3 immunostaining and the functional suppressive activity of Tregs isolated from mesenteric lymph nodes. Results: Foxp3 immunostaining showed that radiation induced a long-term infiltration of the intestine by Tregs (levels 5.5 times greater than in controls). Co-culture of Tregs from mesenteric lymph nodes with CD4{sup +} effector cells showed that the Tregs had lost their suppressive function. This loss was associated with a significant decrease in the levels of Foxp3, TGF-{beta}, and CTLA-4 mRNA, all required for optimal Treg function. At Day 90 after irradiation, Tregs regained their suppressive activity as forkhead box P3 (Foxp3), transforming growth factor beta (TGF-{beta}), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression returned to normal. Analysis of the secretory function of mesenteric lymph node Tregs, activated in vitro with anti-CD3/anti-CD28 Abs, showed that this dysfunction was independent of a defect in interleukin-10 secretion. Conclusion: Radiation caused a long-term accumulation of function-impaired Foxp3{sup +}CD4{sup +} Tregs in the intestine. Our study provides new insights into how radiation affects the immune tolerance in peripheral tissues.},
doi = {10.1016/j.ijrobp.2010.12.041},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 3,
volume = 80,
place = {United States},
year = 2011,
month = 7
}
  • Impairment of the process of absorption of various substances in the small intestine of irradiated animals and man is an important factor in the pathogenesis of radiation lesion to the organism. However, in most studies, data are submitted on impairment of the process of absorption of some nutritional ingredient, and there is no information about impaired absorption of the entire set of main components of nutrition at different postradiation times; many of the works are of a descriptive nature and do not determine the role of trophic changes in the pathogenesis of postradiation disturbances referable to absorption. In view ofmore » the foregoing, it was deemed necessary to study absorption of the main nutritional components--proteins, fats, carbohydrates, and salts in irradiated animals, as well as to determine the significance of disturbances referable to some stages of the digestive and transport systems in the genesis of radiation-induced absorption disorders.« less
  • Studies on the regulation of the enterocytic differentiation of the human colon cancer cell line HT-29, which is differentiated in the absence (Glc/sup -/) but not in the presence of glucose (Glc/sup +/), have recently shown that the post-translational processing of sucrase-isomaltase and particularly its glycosylation vary as a function of cell differentiation. Other studies indicate that in undifferentiated HT-29 Glc/sup +/ cells there is an accumulation of UDP-N-acetylhexosamine, which is involved in the glycosylation process. The purpose of the present work is to investigate whether an overall alteration of protein glycosylation is associated with the inability of HT-29 cellsmore » to differentiate. At least three alterations are detected: (i) after a 10-min pulse, the incorporation of D-(2-/sup 3/H)mannose in undifferentiated cells is severely reduced, compared to differentiated cells. (ii) After a 24-h period of labeling with D-(2-/sup 3/H)mannose, undifferentiated cells accumulate more than 60% of the radioactivity in the high mannose glycopeptides, whereas differentiated HT-29 Glc/sup -/ cells accumulate only 38%. (iii) The analysis of the high mannose oligosaccharides transferred en bloc from the lipid precursor shows that Man/sub 9-8/-GlcNAc/sub 2/ species accumulate in undifferentiated cells, whereas no such accumulation can be detected in differentiated cells. This glycosylation pattern is consistent with an impairment of the trimming of high mannose into complex glycans. It is concluded that N-glycan processing is correlated with the state of enterocytic differentiation of HT-29 cells.« less
  • Micromotility stops within a few hours after general or abdominal irradiation with doses of 200 to 800 r as shown in dogs. The stoppage is preceded by a transient stimulation, which may be avoided by antihistamine and ganglioninhibitor treatment. Motility changes may be produced also in unirradiated dogs with crossed carotis circulation, explicable in terms of a transfer of so-called radiotoxins. If 0.1N HCl is introduced into the duodenum of the starved and irradiated donor animal, this will revive the micromotility of both donor and acceptor within 16 to 24 hours of t of both donor and acceptor within 16more » to 24 hours of the irradiation even if complete paralysis had been produced. Up to 40 hr, the revival may be produced only in the acceptor animal. The ability to respond to hormonal stimulation disappears sooner in the animal suffering direct radiation damage. The clinical significance of the paralysis of micromotility is discussed in relation to early stages of radiation sickness. (OTS)« less
  • Mice were exposed to whole-body gamma radiation and killed at intervals up to 120 days later. Segments of the duodenum were prepared for microscopic examination. Epithelial cells and goblet cells were counted and compared with the number of cells from mice treated with MEA in addition to radiation. Radiation reduced the number of epithelial and goblet cells and there was a marked decrease in the ratio of the latter. The decrease in goblet cells was less marked in mice protected with MEA. (HLW)