PMID- 16493028
OWN - NLM
STAT- MEDLINE
DCOM- 20060428
LR  - 20211203
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 176
IP  - 5
DP  - 2006 Mar 1
TI  - Prolonged TCR/CD28 engagement drives IL-2-independent T cell clonal expansion 
      through signaling mediated by the mammalian target of rapamycin.
PG  - 2730-8
AB  - Proliferation of Ag-specific T cells is central to the development of protective 
      immunity. The concomitant stimulation of the TCR and CD28 programs resting T 
      cells to IL-2-driven clonal expansion. We report that a prolonged occupancy of 
      the TCR and CD28 bypasses the need for autocrine IL-2 secretion and sustains 
      IL-2-independent lymphocyte proliferation. In contrast, a short engagement of the 
      TCR and CD28 only drives the expansion of cells capable of IL-2 production. 
      TCR/CD28- and IL-2-driven proliferation revealed a different requirement for PI3K 
      and for the mammalian target of rapamycin (mTOR). Thus, both PI3K and mTOR 
      activities were needed for T cells to proliferate to TCR/CD28-initiated stimuli 
      and for optimal cyclin E expression. In contrast, either PI3K or mTOR were 
      sufficient for IL-2-driven cell proliferation as they independently mediated 
      cyclin E induction. Interestingly, rapamycin delayed cell cycle entry of 
      IL-2-sufficient T cells, but did not prevent their expansion. Together, our 
      findings indicate that the TCR, CD28, and IL-2 independently control T cell 
      proliferation via distinct signaling pathways involving PI3K and mTOR. These data 
      suggest that Ag persistence and the availability of costimulatory signals and of 
      autocrine and paracrine growth factors individually shape T lymphocyte expansion 
      in vivo.
FAU - Colombetti, Sara
AU  - Colombetti S
AD  - Cancer Immunotherapy and Gene Therapy Program, San Raffaele Scientific Institute, 
      Milan, Italy.
FAU - Basso, Veronica
AU  - Basso V
FAU - Mueller, Daniel L
AU  - Mueller DL
FAU - Mondino, Anna
AU  - Mondino A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (CD28 Antigens)
RN  - 0 (Cyclin D)
RN  - 0 (Cyclin E)
RN  - 0 (Cyclins)
RN  - 0 (Interleukin-2)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - CD28 Antigens/immunology/*metabolism
MH  - Cell Line
MH  - *Cell Proliferation
MH  - Clonal Anergy/immunology
MH  - Clone Cells
MH  - Cyclin D
MH  - Cyclin E/biosynthesis/genetics
MH  - Cyclins/biosynthesis/genetics
MH  - *Interleukin-2/physiology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Phosphatidylinositol 3-Kinases/physiology
MH  - Protein Kinases/*physiology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Antigen, T-Cell/genetics/immunology/*metabolism
MH  - Signal Transduction/*immunology
MH  - T-Lymphocytes/enzymology/*immunology
MH  - TOR Serine-Threonine Kinases
EDAT- 2006/02/24 09:00
MHDA- 2006/04/29 09:00
CRDT- 2006/02/24 09:00
PHST- 2006/02/24 09:00 [pubmed]
PHST- 2006/04/29 09:00 [medline]
PHST- 2006/02/24 09:00 [entrez]
AID - 176/5/2730 [pii]
AID - 10.4049/jimmunol.176.5.2730 [doi]
PST - ppublish
SO  - J Immunol. 2006 Mar 1;176(5):2730-8. doi: 10.4049/jimmunol.176.5.2730.