Limits...
In vivo instruction of suppressor commitment in naive T cells.

Apostolou I, von Boehmer H - J. Exp. Med. (2004)

Bottom Line: The induction of antigen-specific tolerance in the mature immune system of the intact organism has met with limited success.Therefore, nonspecific immunosuppression has been the treatment of choice to prevent unwanted immunity.The described procedure resembles approaches of tolerance induction used decades ago, induces tolerance in the absence of immunity, and holds the promise to become an effective means of inducing antigen-specific tolerance prospectively, whereas its power to suppress already ongoing immune responses remains to be determined.

View Article: PubMed Central - PubMed

Affiliation: Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St., Boston, MA 02115, USA.

ABSTRACT
The induction of antigen-specific tolerance in the mature immune system of the intact organism has met with limited success. Therefore, nonspecific immunosuppression has been the treatment of choice to prevent unwanted immunity. Here, it is shown that prolonged subcutaneous infusion of low doses of peptide by means of osmotic pumps transforms mature T cells into CD4+25+ suppressor cells that can persist for long periods of time in the absence of antigen and confer specific immunologic tolerance upon challenge with antigen. The described procedure resembles approaches of tolerance induction used decades ago, induces tolerance in the absence of immunity, and holds the promise to become an effective means of inducing antigen-specific tolerance prospectively, whereas its power to suppress already ongoing immune responses remains to be determined.

Show MeSH

Related in: MedlinePlus

Long-term survival and Foxp3 expression by CD4+25+ T cells generated from naive T cells. (A) Sorted CD25 negative 6.5+CD4+ T cells from Thy1.1+/+,TCR-HA,RAG-2−/− mice were transferred into BALB/c (Thy1.2+/+) nu/nu recipients implanted with osmotic pumps delivering 10 μg/d of HA peptide for 14 d. Expression of CD25 was monitored at various time points after implantation. (B) Suppressive in vitro activity of CD4+25+ TCR-HA–expressing cells from transferred and pump-implanted nu/nu as well as implanted Tx TCR-HA,RAG-2−/− mice at various time points after delivery of peptide (10 μg/d) for 14 d. (C) Generation of CD4+25+ T cells from CD25 negative Thy1.1+/+RAG-2−/−CD4+6.5+ T cells transferred into normal BALB/c mice that were implanted with peptide-delivery osmotic pumps (10 μg/d). (D) cDNA was prepared from sorted CD25− 6.5+CD4+ and CD25+ 6.5+CD4+ subsets of either pump-implanted Tx TCR-HA,RAG-2−/− mice at day 14 and 16 wk, BALB/c nude mice adoptively transferred with naive CD25−6.5+CD4+ cells from Thy1.1+/+,TCR-HA,RAG-2−/− mice 10 wk after implantation of osmotic pumps delivering peptide for 14 d, naive 6.5+CD4+ cells from TCR-HA,RAG-2−/− mice, or control suppressor CD25+6.5+CD4+ cells of TCR-HA,Ig-HA mice. Foxp3 expression in each of the aforementioned samples was determined by real-time RT-PCR and normalized to its β-actin mRNA levels. Data are representative of at least two independent experiments.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211808&req=5

fig3: Long-term survival and Foxp3 expression by CD4+25+ T cells generated from naive T cells. (A) Sorted CD25 negative 6.5+CD4+ T cells from Thy1.1+/+,TCR-HA,RAG-2−/− mice were transferred into BALB/c (Thy1.2+/+) nu/nu recipients implanted with osmotic pumps delivering 10 μg/d of HA peptide for 14 d. Expression of CD25 was monitored at various time points after implantation. (B) Suppressive in vitro activity of CD4+25+ TCR-HA–expressing cells from transferred and pump-implanted nu/nu as well as implanted Tx TCR-HA,RAG-2−/− mice at various time points after delivery of peptide (10 μg/d) for 14 d. (C) Generation of CD4+25+ T cells from CD25 negative Thy1.1+/+RAG-2−/−CD4+6.5+ T cells transferred into normal BALB/c mice that were implanted with peptide-delivery osmotic pumps (10 μg/d). (D) cDNA was prepared from sorted CD25− 6.5+CD4+ and CD25+ 6.5+CD4+ subsets of either pump-implanted Tx TCR-HA,RAG-2−/− mice at day 14 and 16 wk, BALB/c nude mice adoptively transferred with naive CD25−6.5+CD4+ cells from Thy1.1+/+,TCR-HA,RAG-2−/− mice 10 wk after implantation of osmotic pumps delivering peptide for 14 d, naive 6.5+CD4+ cells from TCR-HA,RAG-2−/− mice, or control suppressor CD25+6.5+CD4+ cells of TCR-HA,Ig-HA mice. Foxp3 expression in each of the aforementioned samples was determined by real-time RT-PCR and normalized to its β-actin mRNA levels. Data are representative of at least two independent experiments.

Mentions: To confirm that the CD4+25+ cells were generated de novo from naive CD4+25− cells rather than representing a population of selected preexisting CD4+25+ cells, CD4+25− cells were sorted from TCR-HA,RAG-2−/− mice and injected into thymus-deficient nu/nu mice that were subsequently implanted with HA peptide–delivering osmotic pumps. The generated CD4+25+ cells could persist up to 10 wk after implantation of pumps (i.e., for 2 mo after termination of peptide delivery), while still being committed to develop suppressive activity after antigenic stimulation in vitro (Fig. 3, A and B). Similarly, CD4+25+ suppressor cells could persist for several months in Tx TCR-HA,RAG-2−/− mice after termination of peptide delivery (Fig. 3 B and not depicted). Thus, like natural suppressors, regulatory T cells obtained by peptide–MHC ligation of the TCR on naive T cells in vivo could persist for long periods of time in the absence of their agonist peptide–MHC complex in the form of CD25+ T cells committed to suppress after renewed stimulation by the TCR ligand.


In vivo instruction of suppressor commitment in naive T cells.

Apostolou I, von Boehmer H - J. Exp. Med. (2004)

Long-term survival and Foxp3 expression by CD4+25+ T cells generated from naive T cells. (A) Sorted CD25 negative 6.5+CD4+ T cells from Thy1.1+/+,TCR-HA,RAG-2−/− mice were transferred into BALB/c (Thy1.2+/+) nu/nu recipients implanted with osmotic pumps delivering 10 μg/d of HA peptide for 14 d. Expression of CD25 was monitored at various time points after implantation. (B) Suppressive in vitro activity of CD4+25+ TCR-HA–expressing cells from transferred and pump-implanted nu/nu as well as implanted Tx TCR-HA,RAG-2−/− mice at various time points after delivery of peptide (10 μg/d) for 14 d. (C) Generation of CD4+25+ T cells from CD25 negative Thy1.1+/+RAG-2−/−CD4+6.5+ T cells transferred into normal BALB/c mice that were implanted with peptide-delivery osmotic pumps (10 μg/d). (D) cDNA was prepared from sorted CD25− 6.5+CD4+ and CD25+ 6.5+CD4+ subsets of either pump-implanted Tx TCR-HA,RAG-2−/− mice at day 14 and 16 wk, BALB/c nude mice adoptively transferred with naive CD25−6.5+CD4+ cells from Thy1.1+/+,TCR-HA,RAG-2−/− mice 10 wk after implantation of osmotic pumps delivering peptide for 14 d, naive 6.5+CD4+ cells from TCR-HA,RAG-2−/− mice, or control suppressor CD25+6.5+CD4+ cells of TCR-HA,Ig-HA mice. Foxp3 expression in each of the aforementioned samples was determined by real-time RT-PCR and normalized to its β-actin mRNA levels. Data are representative of at least two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211808&req=5

fig3: Long-term survival and Foxp3 expression by CD4+25+ T cells generated from naive T cells. (A) Sorted CD25 negative 6.5+CD4+ T cells from Thy1.1+/+,TCR-HA,RAG-2−/− mice were transferred into BALB/c (Thy1.2+/+) nu/nu recipients implanted with osmotic pumps delivering 10 μg/d of HA peptide for 14 d. Expression of CD25 was monitored at various time points after implantation. (B) Suppressive in vitro activity of CD4+25+ TCR-HA–expressing cells from transferred and pump-implanted nu/nu as well as implanted Tx TCR-HA,RAG-2−/− mice at various time points after delivery of peptide (10 μg/d) for 14 d. (C) Generation of CD4+25+ T cells from CD25 negative Thy1.1+/+RAG-2−/−CD4+6.5+ T cells transferred into normal BALB/c mice that were implanted with peptide-delivery osmotic pumps (10 μg/d). (D) cDNA was prepared from sorted CD25− 6.5+CD4+ and CD25+ 6.5+CD4+ subsets of either pump-implanted Tx TCR-HA,RAG-2−/− mice at day 14 and 16 wk, BALB/c nude mice adoptively transferred with naive CD25−6.5+CD4+ cells from Thy1.1+/+,TCR-HA,RAG-2−/− mice 10 wk after implantation of osmotic pumps delivering peptide for 14 d, naive 6.5+CD4+ cells from TCR-HA,RAG-2−/− mice, or control suppressor CD25+6.5+CD4+ cells of TCR-HA,Ig-HA mice. Foxp3 expression in each of the aforementioned samples was determined by real-time RT-PCR and normalized to its β-actin mRNA levels. Data are representative of at least two independent experiments.
Mentions: To confirm that the CD4+25+ cells were generated de novo from naive CD4+25− cells rather than representing a population of selected preexisting CD4+25+ cells, CD4+25− cells were sorted from TCR-HA,RAG-2−/− mice and injected into thymus-deficient nu/nu mice that were subsequently implanted with HA peptide–delivering osmotic pumps. The generated CD4+25+ cells could persist up to 10 wk after implantation of pumps (i.e., for 2 mo after termination of peptide delivery), while still being committed to develop suppressive activity after antigenic stimulation in vitro (Fig. 3, A and B). Similarly, CD4+25+ suppressor cells could persist for several months in Tx TCR-HA,RAG-2−/− mice after termination of peptide delivery (Fig. 3 B and not depicted). Thus, like natural suppressors, regulatory T cells obtained by peptide–MHC ligation of the TCR on naive T cells in vivo could persist for long periods of time in the absence of their agonist peptide–MHC complex in the form of CD25+ T cells committed to suppress after renewed stimulation by the TCR ligand.

Bottom Line: The induction of antigen-specific tolerance in the mature immune system of the intact organism has met with limited success.Therefore, nonspecific immunosuppression has been the treatment of choice to prevent unwanted immunity.The described procedure resembles approaches of tolerance induction used decades ago, induces tolerance in the absence of immunity, and holds the promise to become an effective means of inducing antigen-specific tolerance prospectively, whereas its power to suppress already ongoing immune responses remains to be determined.

View Article: PubMed Central - PubMed

Affiliation: Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St., Boston, MA 02115, USA.

ABSTRACT
The induction of antigen-specific tolerance in the mature immune system of the intact organism has met with limited success. Therefore, nonspecific immunosuppression has been the treatment of choice to prevent unwanted immunity. Here, it is shown that prolonged subcutaneous infusion of low doses of peptide by means of osmotic pumps transforms mature T cells into CD4+25+ suppressor cells that can persist for long periods of time in the absence of antigen and confer specific immunologic tolerance upon challenge with antigen. The described procedure resembles approaches of tolerance induction used decades ago, induces tolerance in the absence of immunity, and holds the promise to become an effective means of inducing antigen-specific tolerance prospectively, whereas its power to suppress already ongoing immune responses remains to be determined.

Show MeSH
Related in: MedlinePlus