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 language | English (US) |
|---|---|
| Pages (from-to) | 21629-21634 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 107 |
| Issue number | 50 |
| DOIs | |
| State | Published - Dec 14 2010 |
| Externally published | Yes |
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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 journal › Article
}
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 -