Dicer controls CD8+ T-cell activation, migration, and survival

Nu Zhang, Michael J. Bevan

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

The RNaseIII enzyme Dicer is required for mature microRNA production. Although extensive investigation has been carried out to determine the role of Dicer/miRNAs in the immune system, their function in mature CD8+ T cells has not been examined. We deleted Dicer in mature polyclonal and TCR transgenic CD8+ T cells using either tat-cre or the distal lck promoter, which drives cre expression after the stage of positive selection. Following antigenic challenge by a pathogen infection in vivo, Dicer-deleted CD8+ T cells failed to accumulate at the usual peak of the response. Surprisingly however, we found that deletion of Dicer in mature CD8+ T cells allowed them to respond more rapidly than control cells to TCR stimuli in vitro. In response to anti-CD3 plus anti-CD28 stimulation, Dicer-deleted T cells up-regulated CD69 faster and entered the first mitosis earlier than control T cells. In addition, activated Dicer-/- cells failed to rapidly down-regulate CD69 when removed from the TCR stimulus. As a probable consequence of this sustained CD69 expression, Dicer-/- T cells showed defective migration out of the central lymphoid organs in vivo. We identify miR-130/301, which are dramatically up-regulated following T-cell activation as able to down-regulate CD69 expressio n via bindingto a conserved site in the 3'UTR of CD69 mRNA. Thus, cellular functions dependent on Dicer expression are not required for the early steps in CD8+ T-cell activation, but are essential for their survival and accumulation.

Original languageEnglish (US)
Pages (from-to)21629-21634
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number50
DOIs
StatePublished - Dec 14 2010
Externally publishedYes

Fingerprint

Cell Movement
Cell Survival
T-Lymphocytes
MicroRNAs
Down-Regulation
Ribonuclease III
3' Untranslated Regions
Mitosis
Immune System
Messenger RNA
Infection

Keywords

  • Listeria
  • Tat-cre
  • Vesicular stomatitis virus

ASJC Scopus subject areas

  • General

Cite this

Dicer controls CD8+ T-cell activation, migration, and survival. / Zhang, Nu; Bevan, Michael J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 50, 14.12.2010, p. 21629-21634.

Research output: Contribution to journalArticle

@article{63f56fcdebc540e290cc9bf0eb0f1cb3,
title = "Dicer controls CD8+ T-cell activation, migration, and survival",
abstract = "The RNaseIII enzyme Dicer is required for mature microRNA production. Although extensive investigation has been carried out to determine the role of Dicer/miRNAs in the immune system, their function in mature CD8+ T cells has not been examined. We deleted Dicer in mature polyclonal and TCR transgenic CD8+ T cells using either tat-cre or the distal lck promoter, which drives cre expression after the stage of positive selection. Following antigenic challenge by a pathogen infection in vivo, Dicer-deleted CD8+ T cells failed to accumulate at the usual peak of the response. Surprisingly however, we found that deletion of Dicer in mature CD8+ T cells allowed them to respond more rapidly than control cells to TCR stimuli in vitro. In response to anti-CD3 plus anti-CD28 stimulation, Dicer-deleted T cells up-regulated CD69 faster and entered the first mitosis earlier than control T cells. In addition, activated Dicer-/- cells failed to rapidly down-regulate CD69 when removed from the TCR stimulus. As a probable consequence of this sustained CD69 expression, Dicer-/- T cells showed defective migration out of the central lymphoid organs in vivo. We identify miR-130/301, which are dramatically up-regulated following T-cell activation as able to down-regulate CD69 expressio n via bindingto a conserved site in the 3'UTR of CD69 mRNA. Thus, cellular functions dependent on Dicer expression are not required for the early steps in CD8+ T-cell activation, but are essential for their survival and accumulation.",
keywords = "Listeria, Tat-cre, Vesicular stomatitis virus",
author = "Nu Zhang and Bevan, {Michael J.}",
year = "2010",
month = "12",
day = "14",
doi = "10.1073/pnas.1016299107",
language = "English (US)",
volume = "107",
pages = "21629--21634",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "50",

}

TY - JOUR

T1 - Dicer controls CD8+ T-cell activation, migration, and survival

AU - Zhang, Nu

AU - Bevan, Michael J.

PY - 2010/12/14

Y1 - 2010/12/14

N2 - The RNaseIII enzyme Dicer is required for mature microRNA production. Although extensive investigation has been carried out to determine the role of Dicer/miRNAs in the immune system, their function in mature CD8+ T cells has not been examined. We deleted Dicer in mature polyclonal and TCR transgenic CD8+ T cells using either tat-cre or the distal lck promoter, which drives cre expression after the stage of positive selection. Following antigenic challenge by a pathogen infection in vivo, Dicer-deleted CD8+ T cells failed to accumulate at the usual peak of the response. Surprisingly however, we found that deletion of Dicer in mature CD8+ T cells allowed them to respond more rapidly than control cells to TCR stimuli in vitro. In response to anti-CD3 plus anti-CD28 stimulation, Dicer-deleted T cells up-regulated CD69 faster and entered the first mitosis earlier than control T cells. In addition, activated Dicer-/- cells failed to rapidly down-regulate CD69 when removed from the TCR stimulus. As a probable consequence of this sustained CD69 expression, Dicer-/- T cells showed defective migration out of the central lymphoid organs in vivo. We identify miR-130/301, which are dramatically up-regulated following T-cell activation as able to down-regulate CD69 expressio n via bindingto a conserved site in the 3'UTR of CD69 mRNA. Thus, cellular functions dependent on Dicer expression are not required for the early steps in CD8+ T-cell activation, but are essential for their survival and accumulation.

AB - The RNaseIII enzyme Dicer is required for mature microRNA production. Although extensive investigation has been carried out to determine the role of Dicer/miRNAs in the immune system, their function in mature CD8+ T cells has not been examined. We deleted Dicer in mature polyclonal and TCR transgenic CD8+ T cells using either tat-cre or the distal lck promoter, which drives cre expression after the stage of positive selection. Following antigenic challenge by a pathogen infection in vivo, Dicer-deleted CD8+ T cells failed to accumulate at the usual peak of the response. Surprisingly however, we found that deletion of Dicer in mature CD8+ T cells allowed them to respond more rapidly than control cells to TCR stimuli in vitro. In response to anti-CD3 plus anti-CD28 stimulation, Dicer-deleted T cells up-regulated CD69 faster and entered the first mitosis earlier than control T cells. In addition, activated Dicer-/- cells failed to rapidly down-regulate CD69 when removed from the TCR stimulus. As a probable consequence of this sustained CD69 expression, Dicer-/- T cells showed defective migration out of the central lymphoid organs in vivo. We identify miR-130/301, which are dramatically up-regulated following T-cell activation as able to down-regulate CD69 expressio n via bindingto a conserved site in the 3'UTR of CD69 mRNA. Thus, cellular functions dependent on Dicer expression are not required for the early steps in CD8+ T-cell activation, but are essential for their survival and accumulation.

KW - Listeria

KW - Tat-cre

KW - Vesicular stomatitis virus

UR - http://www.scopus.com/inward/record.url?scp=78650754295&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650754295&partnerID=8YFLogxK

U2 - 10.1073/pnas.1016299107

DO - 10.1073/pnas.1016299107

M3 - Article

C2 - 21098294

AN - SCOPUS:78650754295

VL - 107

SP - 21629

EP - 21634

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 50

ER -