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Regulatory CD4⁺CD25⁺ cells reverse imbalances in the T cell pool of bone marrow transplanted TG26 mice leading to the prevention of colitis

¹ Department of Gastroenterology, Ruprecht-Karls-University, Heidelberg, Germany
² Center for GI Biology and Disease, University of North Carolina, Chapel Hill, NC, USA
³ Department of Immunology, Ruprecht-Karls-University, Heidelberg, Germany
⁴ Department of Pathology, Ruprecht-Karls-University, Heidelberg, Germany
⁵ Department of Neurology, Ruprecht-Karls-University, Heidelberg, Germany

Correspondence to:
Correspondence to:
Dr C Veltkamp
Department of Gastroenterology, University of Heidelberg, INF 410, 69120 Heidelberg, Germany; Claudia_veltkamp{at}med.uni-heidelberg.de

ABSTRACT
Background and aims: Erroneous thymic selection of developing T lymphocytes may be responsible for the expansion of self reactive T cells or may contribute to the absence of regulatory T cells important in controlling peripheral inflammatory processes. Colitis in bone marrow (BM) transplanted Tg26 mice is induced by abnormally activated T cells developing in an aberrant thymic microenvironment. We investigated the protective role of regulatory CD4⁺CD25⁺ T cells in this model.

Methods: BM from (C57BL/6xCBA/J) F1 mice was transplanted into specific pathogen free Tg26 mice (BMTg26). Transplanted mice received no cells (control), sorted CD4⁺CD25⁺, or CD4⁺CD25^– cells from mesenteric lymph nodes (MLN) of normal mice. MLN cell subsets were analysed using membrane markers. Cytokine secretion of MLN cells was measured using intracellular cytokine staining and cytokine secretion in anti-CD3 stimulated cell cultures. Colitis was measured by histological scores.

Results: CD4⁺CD25⁺ cells were reduced in the MLNs of BMTg26 mice. Transfer of regulatory CD4⁺CD25⁺ but not of CD4⁺CD25^– cells reduced the number of MLN CD4⁺ T cells in BMTg26 recipients and increased the number of MLN CD8⁺ cells, thereby normalising the CD4⁺/CD8⁺ ratio. CD4⁺CD25⁺ but not CD4⁺CD25^– cell transfer into BMTg26 mice reduced the number of tumour necrosis factor ⁺ CD4⁺ cells and increased the secretion of transforming growth factor ß by MLN cells. Transfer of 3x10⁵ CD4⁺CD25⁺ cells after BM transplantation into Tg26 mice prevented colitis whereas CD4⁺CD25^– cells had no protective effect.

Conclusions: These results suggest that defective selection or induction of regulatory T cells in the abnormal thymus is responsible for the development of colitis in BMTg26 mice. Transfer of CD4⁺CD25⁺ cells can control intestinal inflammation in BMTg26 mice by normalising the number and function of the MLN T cell pool.

Abbreviations: BM, bone marrow; BMTg26, Tg26 mice transplanted with wild-type bone marrow; FITC, fluorescein isothiocyanate; IFN, interferon; IL, interleukin; MLN, mesenteric lymph node; SPF, specific pathogen free; Th1, T helper 1; TNF, tumour necrosis factor; Treg cells, regulatory T cells; TGF-ß, transforming growth factor ß

Keywords: T lymphocytes; cytokines; TG26 mice; experimental colitis