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Knockdown of T-bet expression in Mart-127-35 -specific T-cell-receptor-engineered human CD4(+) CD25(-) and CD8(+) T cells attenuates effector function.

Abstract：

:Gene transfer to create tumour epitope-specific cytolytic T cells for adoptive immunotherapy of cancer remains an area of active inquiry. When the Mart-127-35 -specific DMF5 T-cell receptor (TCR) is transferred into peripheral human CD4(+) T cells, the reprogrammed cells exhibit a T helper type 1 (Th1) phenotype with significant multifactorial effector capabilities. The T-bet transcription factor plays an important role in determination of the Th1 differentiation pathway. To gain a deeper understanding of how T-bet controls the outcome of human T-cell reprogramming by gene transfer, we developed a system for examining the effects of short hairpin RNA-mediated T-bet gene knockdown in sorted cell populations uniformly expressing the knockdown construct. In this system, using activated peripheral human CD4(+) CD25(-) and CD8(+) T cells, T-bet knockdown led to attenuation of the interferon-γ response to both antigen-specific and non-specific TCR stimulation. The interleukin-2 (IL-2) antigen-specific response was not attenuated by T-bet knockdown. Also, in TCR-reprogrammed CD8(+) cells, the cytolytic effector response was attenuated by T-bet knockdown. T-bet knockdown did not cause redirection into a Th2 differentiation pathway, and no increased IL-4, IL-10, or IL-17 response was detected in this system. These results indicate that T-bet expression is required for maintenance of the CD4(+) CD25(-) and CD8(+) effector phenotypes in TCR-reprogrammed human T cells. They also suggest that the activation protocol necessary for transduction with retrovectors and lentivectors may commit the reprogrammed cells to the Th1 phenotype, which cannot be altered by T-bet knockdown but that there is, nevertheless, a continuous requirement of T-bet expression for interferon-γ gene activation.

journal_name

Immunology

journal_title

Immunology

authors

Jha SS,Chakraborty NG,Singh P,Mukherji B,Dorsky DI

doi

10.1111/imm.12431

subject

Has Abstract

pub_date

2015-05-01 00:00:00

pages

124-35

issue

eissn

0019-2805

issn

1365-2567

journal_volume

145

pub_type

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Knockdown of T-bet expression in Mart-127-35 -specific T-cell-receptor-engineered human CD4(+) CD25(-) and CD8(+) T cells attenuates effector function.