Distinct pathways involving the FK506-binding proteins 12 and 12.6 underlie IL-2- versus IL-15-mediated proliferation of T cells

Sigrid Dubois, Weinian Shou, Laura Haneline, Sidney Fleischer, Thomas A. Waldmann, Jürgen R. Müller

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The molecular basis for the different roles of IL-2 and IL-15 in lymphocyte function has been poorly defined. Searching for differences that underlie the distinct T cell responses to the two cytokines, we observed a marked susceptibility of the IL-15-induced but not of the IL-2-induced proliferation to rapamycin despite a decrease of p70S6 kinase (p70 S6K) activation by the drug in response to both cytokines. Activated splenic T lymphocytes deficient in the FK506-binding protein (FKBP) 12, a target of rapamycin activity, had reduced proliferation in response to IL-15 but not to IL-2. This decreased proliferation was accompanied by reduced activation of p70S6K and of the extracellular signal-regulated kinases (ERK) after IL-15 treatment. In contrast to FKBP12-/- cells, splenic FKBP12.6-/- T cells exhibited a decreased proliferative response to IL-2 in the presence of rapamycin without affecting p70 S6K or ERK activation. Thus, IL-15 induces T cell proliferation mainly via FKBP12-mediated p70S6K activation. In contrast, IL-2 signaling involves multiple pathways that include at least one additional pathway that depends on FKBP12.6.

Original languageEnglish
Pages (from-to)14169-14174
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue numberSUPPL. 2
DOIs
StatePublished - Nov 25 2003

Fingerprint

Tacrolimus Binding Proteins
Interleukin-15
Interleukin-2
T-Lymphocytes
Sirolimus
Tacrolimus Binding Protein 1A
70-kDa Ribosomal Protein S6 Kinases
Extracellular Signal-Regulated MAP Kinases
Phosphotransferases
Cytokines
Cell Proliferation
Lymphocytes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Distinct pathways involving the FK506-binding proteins 12 and 12.6 underlie IL-2- versus IL-15-mediated proliferation of T cells. / Dubois, Sigrid; Shou, Weinian; Haneline, Laura; Fleischer, Sidney; Waldmann, Thomas A.; Müller, Jürgen R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. SUPPL. 2, 25.11.2003, p. 14169-14174.

Research output: Contribution to journalArticle

@article{06a0e88a7ba34d8e9d8ccbad0c0b3f9f,
title = "Distinct pathways involving the FK506-binding proteins 12 and 12.6 underlie IL-2- versus IL-15-mediated proliferation of T cells",
abstract = "The molecular basis for the different roles of IL-2 and IL-15 in lymphocyte function has been poorly defined. Searching for differences that underlie the distinct T cell responses to the two cytokines, we observed a marked susceptibility of the IL-15-induced but not of the IL-2-induced proliferation to rapamycin despite a decrease of p70S6 kinase (p70 S6K) activation by the drug in response to both cytokines. Activated splenic T lymphocytes deficient in the FK506-binding protein (FKBP) 12, a target of rapamycin activity, had reduced proliferation in response to IL-15 but not to IL-2. This decreased proliferation was accompanied by reduced activation of p70S6K and of the extracellular signal-regulated kinases (ERK) after IL-15 treatment. In contrast to FKBP12-/- cells, splenic FKBP12.6-/- T cells exhibited a decreased proliferative response to IL-2 in the presence of rapamycin without affecting p70 S6K or ERK activation. Thus, IL-15 induces T cell proliferation mainly via FKBP12-mediated p70S6K activation. In contrast, IL-2 signaling involves multiple pathways that include at least one additional pathway that depends on FKBP12.6.",
author = "Sigrid Dubois and Weinian Shou and Laura Haneline and Sidney Fleischer and Waldmann, {Thomas A.} and M{\"u}ller, {J{\"u}rgen R.}",
year = "2003",
month = "11",
day = "25",
doi = "10.1073/pnas.2335979100",
language = "English",
volume = "100",
pages = "14169--14174",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "SUPPL. 2",

}

TY - JOUR

T1 - Distinct pathways involving the FK506-binding proteins 12 and 12.6 underlie IL-2- versus IL-15-mediated proliferation of T cells

AU - Dubois, Sigrid

AU - Shou, Weinian

AU - Haneline, Laura

AU - Fleischer, Sidney

AU - Waldmann, Thomas A.

AU - Müller, Jürgen R.

PY - 2003/11/25

Y1 - 2003/11/25

N2 - The molecular basis for the different roles of IL-2 and IL-15 in lymphocyte function has been poorly defined. Searching for differences that underlie the distinct T cell responses to the two cytokines, we observed a marked susceptibility of the IL-15-induced but not of the IL-2-induced proliferation to rapamycin despite a decrease of p70S6 kinase (p70 S6K) activation by the drug in response to both cytokines. Activated splenic T lymphocytes deficient in the FK506-binding protein (FKBP) 12, a target of rapamycin activity, had reduced proliferation in response to IL-15 but not to IL-2. This decreased proliferation was accompanied by reduced activation of p70S6K and of the extracellular signal-regulated kinases (ERK) after IL-15 treatment. In contrast to FKBP12-/- cells, splenic FKBP12.6-/- T cells exhibited a decreased proliferative response to IL-2 in the presence of rapamycin without affecting p70 S6K or ERK activation. Thus, IL-15 induces T cell proliferation mainly via FKBP12-mediated p70S6K activation. In contrast, IL-2 signaling involves multiple pathways that include at least one additional pathway that depends on FKBP12.6.

AB - The molecular basis for the different roles of IL-2 and IL-15 in lymphocyte function has been poorly defined. Searching for differences that underlie the distinct T cell responses to the two cytokines, we observed a marked susceptibility of the IL-15-induced but not of the IL-2-induced proliferation to rapamycin despite a decrease of p70S6 kinase (p70 S6K) activation by the drug in response to both cytokines. Activated splenic T lymphocytes deficient in the FK506-binding protein (FKBP) 12, a target of rapamycin activity, had reduced proliferation in response to IL-15 but not to IL-2. This decreased proliferation was accompanied by reduced activation of p70S6K and of the extracellular signal-regulated kinases (ERK) after IL-15 treatment. In contrast to FKBP12-/- cells, splenic FKBP12.6-/- T cells exhibited a decreased proliferative response to IL-2 in the presence of rapamycin without affecting p70 S6K or ERK activation. Thus, IL-15 induces T cell proliferation mainly via FKBP12-mediated p70S6K activation. In contrast, IL-2 signaling involves multiple pathways that include at least one additional pathway that depends on FKBP12.6.

UR - http://www.scopus.com/inward/record.url?scp=0344198591&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0344198591&partnerID=8YFLogxK

U2 - 10.1073/pnas.2335979100

DO - 10.1073/pnas.2335979100

M3 - Article

C2 - 14605212

AN - SCOPUS:0344198591

VL - 100

SP - 14169

EP - 14174

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 - SUPPL. 2

ER -