Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome. / Krejsgaard, T; Gjerdrum, L M; Ralfkiaer, E; Lauenborg, B; Eriksen, K W; Mathiesen, A-M; Bovin, L F; Gniadecki, R; Geisler, C; Ryder, L P; Zhang, Q; Wasik, M A; Odum, Niels; Woetmann, A.
In: Leukemia, 2008, p. 2230-2239.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome
AU - Krejsgaard, T
AU - Gjerdrum, L M
AU - Ralfkiaer, E
AU - Lauenborg, B
AU - Eriksen, K W
AU - Mathiesen, A-M
AU - Bovin, L F
AU - Gniadecki, R
AU - Geisler, C
AU - Ryder, L P
AU - Zhang, Q
AU - Wasik, M A
AU - Odum, Niels
AU - Woetmann, A
PY - 2008
Y1 - 2008
N2 - Sézary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3 in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-beta and suppress the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-kappaB (NF-kappaB) activity in reporter assays which is in keeping with a constitutive NF-kappaB activity in the malignant T cells. In conclusion, we show that the malignant T cells express low molecular splice forms of FOXP3 and function as Tregs. Furthermore, we provide evidence that FOXP3 splice forms are functionally different from wt FOXP3 and not involved in the execution of the suppressive function. Thus, this is the first description of FOXP3 splice forms in human disease.Leukemia advance online publication, 4 September 2008; doi:10.1038/leu.2008.224.
AB - Sézary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3 in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-beta and suppress the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-kappaB (NF-kappaB) activity in reporter assays which is in keeping with a constitutive NF-kappaB activity in the malignant T cells. In conclusion, we show that the malignant T cells express low molecular splice forms of FOXP3 and function as Tregs. Furthermore, we provide evidence that FOXP3 splice forms are functionally different from wt FOXP3 and not involved in the execution of the suppressive function. Thus, this is the first description of FOXP3 splice forms in human disease.Leukemia advance online publication, 4 September 2008; doi:10.1038/leu.2008.224.
U2 - 10.1038/leu.2008.224
DO - 10.1038/leu.2008.224
M3 - Journal article
C2 - 18769452
SP - 2230
EP - 2239
JO - Leukemia
JF - Leukemia
SN - 0887-6924
ER -
ID: 8544016