TGF-ß upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma.
Leukemia
; 28(9): 1872-84, 2014 Sep.
Article
em En
| MEDLINE
| ID: mdl-24569779
ABSTRACT
Transforming growth factor beta (TGF-ß) has an important role in mediating T-cell suppression in B-cell non-Hodgkin lymphoma (NHL). However, the underlying mechanism responsible for TGF-ß-mediated inhibition of effector memory T (Tm) cells is largely unknown. As reported here, we show that exhaustion is a major mechanism by which TGF-ß inhibits Tm cells, and TGF-ß mediated exhaustion is associated with upregulation of CD70. We found that TGF-ß upregulates CD70 expression on effector Tm cells while it preferentially induces Foxp3 expression in naive T cells. CD70 induction by TGF-ß is Smad3-dependent and involves IL-2/Stat5 signaling. CD70+ T cells account for TGF-ß-induced exhaustion of effector Tm cells. Both TGF-ß-induced and preexisting intratumoral CD70+ effector Tm cells from B-cell NHL have an exhausted phenotype and express higher levels of PD-1 and TIM-3 compared with CD70- T cells. Signaling transduction, proliferation and cytokine production are profoundly decreased in these cells, and they are highly susceptible to apoptosis. Clinically, intratumoral CD70-expressing T cells are prevalent in follicular B-cell lymphoma (FL) biopsy specimens, and increased numbers of intratumoral CD70+ T cells correlate with an inferior patient outcome. These findings confirm TGF-ß-mediated effector Tm cell exhaustion as an important mechanism of immune suppression in B-cell NHL.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T
/
Linfoma de Células B
/
Fator de Crescimento Transformador beta
/
Ligante CD27
/
Memória Imunológica
Limite:
Humans
Idioma:
En
Revista:
Leukemia
Assunto da revista:
HEMATOLOGIA
/
NEOPLASIAS
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos