Abdominal γ-radiation induces an accumulation of function-impaired regulatory t cells in the small intestine

F. Billiard (1) , V. Buard (1) , M. Benderitter (1) , C. Linard (1)

1 IRSN/PRP-HOM/SRBE/LRTOX - Laboratoire de radiotoxicologie et radiobiologie expérimentale

Purpose: To assess the frequency and the functional characteristics of one major component of immune tolerance, the CD4+FoxP3+ regulatory T cells (Tregs) in a mouse model of abdominal irradiation. Methods and Materials: Mice were exposed to a single abdominal dose of γ-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+ 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-β, 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-β), 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+CD4+ Tregs in the intestine. Our study provides new insights into how radiation affects the immune tolerance in peripheral tissues. © 2011 Elsevier Inc.

Mots clés: Abdominal irradiation; Coculture; Cytotoxic; Effector cells; Functional characteristics; Immune tolerance; Immune tolerances; Immunostaining; In-control; In-vitro; Interleukin-10; Intestine; Lymph node; Mouse models; Peripheral tissue; Radiation-induced; Small intestine; T cells; Transforming growth factor beta; Body fluids; Cell culture; Irradiation; Seepage; Soil mechanics; Tissue; Radiation; CD3 antibody; cytotoxic T lymphocyte antigen 4; interleukin 10; messenger RNA; monoclonal antibody CD28; transcription factor FOXP3; transforming growth factor beta; article; cell infiltration; gamma radiation; immunohistochemistry; in vitro study; mesentery lymph node; mouse; nonhuman; priority journal; protein expression; regulatory T lymphocyte; small intestine; Abdomen; Animals; Antigens; CD; Forkhead Transcription Factors; Gamma Rays; Immune Tolerance; Immunity; Cellular; Small; Lymph Nodes; Mesentery; Mice; Inbred C57BL; Radiation Dosage; RNA; Messenger; T-Lymphocytes; Regulatory; Transforming Growth Factor beta

Domaines: Sciences du Vivant [q-bio]

F. Billiard, V. Buard, M. Benderitter, C. Linard. Abdominal γ-radiation induces an accumulation of function-impaired regulatory t cells in the small intestine. International Journal of Radiation Oncology, Biology, Physics, 2011, 80 (3), pp.869-876. ⟨10.1016/j.ijrobp.2010.12.041⟩. ⟨hal-02954934⟩