TGFbeta regulates the CD4+CD25+ T-cell pool and the expression of Foxp3 in vivo

TY - JOUR

T1 - TGFbeta regulates the CD4+CD25+ T-cell pool and the expression of Foxp3 in vivo

AU - Schramm, Christoph

AU - Huber, Samuel

AU - Protschka, Martina

AU - Czochra, P

AU - Burg, Jürgen

AU - Schmitt, Edgar

AU - Lohse, Ansgar W

AU - Galle, Peter R

AU - Blessing, Manfred

PY - 2004/9

Y1 - 2004/9

N2 - Factors influencing the development of CD4+CD25+ T-cells in vivo are poorly understood. In order to investigate the contribution of TGFbeta1 to the development and function of CD4+CD25+ T-cells, we generated a gain of function mutation resulting in the overexpression of an active form of TGFbeta1 in T-cells under control of the human CD2 promoter. In peripheral lymphoid organs and in the thymus, the frequency of CD4+CD25+ T-cells was increased in transgenic mice. This appeared to be due to an autocrine effect of TGFbeta on T-cells, since concomitant impairment of TGFbeta-signaling in double transgenic mice resulted in a phenotype similar to wild type. In contrast, in single transgenic mice with impaired TGFbeta-signaling in T-cells, CD4+CD25+ T-cell numbers were reduced in peripheral lymphoid organs but not in the thymus. In addition, TGFbeta was found to regulate the expression of Foxp3 in vivo, a transcription factor essential for the generation and function of regulatory T-cells. In CD4+CD25+ T-cells, TGFbeta1 increased the expression of Foxp3, whereas a decreased expression was seen in CD4+CD25+ T-cells with impaired TGFbeta-signaling. TGFbeta1 induced the expression of IL-10 in transgenic T-cells, but the increased in vitro suppressive capacity observed in transgenic CD4+CD25+ T-cells was due to the secretion of TGFbeta and not IL-10. Therefore, our study provides in vivo evidence for a role of TGFbeta in the homeostasis of CD4+CD25+ T-cells.

AB - Factors influencing the development of CD4+CD25+ T-cells in vivo are poorly understood. In order to investigate the contribution of TGFbeta1 to the development and function of CD4+CD25+ T-cells, we generated a gain of function mutation resulting in the overexpression of an active form of TGFbeta1 in T-cells under control of the human CD2 promoter. In peripheral lymphoid organs and in the thymus, the frequency of CD4+CD25+ T-cells was increased in transgenic mice. This appeared to be due to an autocrine effect of TGFbeta on T-cells, since concomitant impairment of TGFbeta-signaling in double transgenic mice resulted in a phenotype similar to wild type. In contrast, in single transgenic mice with impaired TGFbeta-signaling in T-cells, CD4+CD25+ T-cell numbers were reduced in peripheral lymphoid organs but not in the thymus. In addition, TGFbeta was found to regulate the expression of Foxp3 in vivo, a transcription factor essential for the generation and function of regulatory T-cells. In CD4+CD25+ T-cells, TGFbeta1 increased the expression of Foxp3, whereas a decreased expression was seen in CD4+CD25+ T-cells with impaired TGFbeta-signaling. TGFbeta1 induced the expression of IL-10 in transgenic T-cells, but the increased in vitro suppressive capacity observed in transgenic CD4+CD25+ T-cells was due to the secretion of TGFbeta and not IL-10. Therefore, our study provides in vivo evidence for a role of TGFbeta in the homeostasis of CD4+CD25+ T-cells.

KW - Animals

KW - CD2 Antigens/physiology

KW - CD4 Antigens/analysis

KW - DNA-Binding Proteins/analysis

KW - Forkhead Transcription Factors

KW - Interleukin-10/biosynthesis

KW - Mice

KW - Mice, Transgenic

KW - Receptors, Interleukin-2/analysis

KW - T-Lymphocyte Subsets/physiology

KW - Transforming Growth Factor beta/physiology

U2 - 10.1093/intimm/dxh126

DO - 10.1093/intimm/dxh126

M3 - SCORING: Journal article

C2 - 15249539

VL - 16

SP - 1241

EP - 1249

JO - INT IMMUNOL

JF - INT IMMUNOL

SN - 0953-8178

IS - 9

ER -