TGF-Β upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma

Z. Z. Yang, D. M. Grote, B. Xiu, S. C. Ziesmer, T. L. Price-Troska, L. S. Hodge, D. M. Yates, Anne J Novak, Stephen Maxted Ansell

Research output: Contribution to journalArticle

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Abstract

Transforming growth factor beta (TGF-Β) has an important role in mediating T-cell suppression in B-cell non-Hodgkin lymphoma (NHL). However, the underlying mechanism responsible for TGF-Β-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-Β inhibits Tm cells, and TGF-Β mediated exhaustion is associated with upregulation of CD70. We found that TGF-Β upregulates CD70 expression on effector T m cells while it preferentially induces Foxp3 expression in naive T cells. CD70 induction by TGF-Β is Smad3-dependent and involves IL-2/Stat5 signaling. CD70+ T cells account for TGF-Β-induced exhaustion of effector Tm cells. Both TGF-Β-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-Β-mediated effector T m cell exhaustion as an important mechanism of immune suppression in B-cell NHL.

Original languageEnglish (US)
Pages (from-to)1872-1884
Number of pages13
JournalLeukemia
Volume28
Issue number9
DOIs
StatePublished - 2014

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B-Cell Lymphoma
Transforming Growth Factor beta
Non-Hodgkin's Lymphoma
Up-Regulation
T-Lymphocytes
Follicular Lymphoma
Interleukin-2
Apoptosis
Cytokines
Phenotype
Biopsy

ASJC Scopus subject areas

  • Cancer Research
  • Anesthesiology and Pain Medicine
  • Hematology

Cite this

TGF-Β upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma. / Yang, Z. Z.; Grote, D. M.; Xiu, B.; Ziesmer, S. C.; Price-Troska, T. L.; Hodge, L. S.; Yates, D. M.; Novak, Anne J; Ansell, Stephen Maxted.

In: Leukemia, Vol. 28, No. 9, 2014, p. 1872-1884.

Research output: Contribution to journalArticle

Yang, ZZ, Grote, DM, Xiu, B, Ziesmer, SC, Price-Troska, TL, Hodge, LS, Yates, DM, Novak, AJ & Ansell, SM 2014, 'TGF-Β upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma', Leukemia, vol. 28, no. 9, pp. 1872-1884. https://doi.org/10.1038/leu.2014.84
Yang, Z. Z. ; Grote, D. M. ; Xiu, B. ; Ziesmer, S. C. ; Price-Troska, T. L. ; Hodge, L. S. ; Yates, D. M. ; Novak, Anne J ; Ansell, Stephen Maxted. / TGF-Β upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma. In: Leukemia. 2014 ; Vol. 28, No. 9. pp. 1872-1884.
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