Cyclophilin A regulates TCR signal strength in CD4+ T cells via a proline-directed conformational switch in Itk

John Colgan; Mohammed Asmal; Martha Neagu; Bin Yu; Jason Schneidkraut; Youngnam Lee; Elena Sokolskaja; Amy Andreotti; Jeremy Luban

doi:10.1016/j.immuni.2004.07.005

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Cyclophilin A regulates TCR signal strength in CD4+ T cells via a proline-directed conformational switch in Itk

Journal article

Open access

Peer reviewed

Cyclophilin A regulates TCR signal strength in CD4+ T cells via a proline-directed conformational switch in Itk

John Colgan, Mohammed Asmal, Martha Neagu, Bin Yu, Jason Schneidkraut, Youngnam Lee, Elena Sokolskaja, Amy Andreotti and Jeremy Luban

Immunity (Cambridge, Mass.), Vol.21(2), pp.189-201

08/2004

DOI: 10.1016/j.immuni.2004.07.005

PMID: 15308100

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Abstract

Cyclophilin A (CypA/Ppia) is a peptidyl-prolyl isomerase (PPIase) that binds the immunosuppressive drug cyclosporine. The resulting complex blocks T cell function by inhibiting the calcium-dependent phosphatase calcineurin. To identify the native function of CypA, long suspected of regulating signal transduction, we generated mice lacking the Ppia gene. These animals develop allergic disease, with elevated IgE and tissue infiltration by mast cells and eosinophils, that is driven by CD4+ T helper type II (Th2) cytokines. Ppia(-/-) Th2 cells were hypersensitive to TCR stimulation, a phenotype consistent with increased activity of Itk, a Tec family tyrosine kinase crucial for Th2 responses. CypA bound Itk via the PPIase active site. Mutation of a conformationally heterogeneous proline in the SH2 domain of Itk disrupted interaction with CypA and specifically increased Th2 cytokine production from wild-type CD4+ T cells. Thus, CypA inhibits CD4+ T cell signal transduction in the absence of cyclosporine via a regulatory proline residue in Itk.

Cyclophilin A - metabolism

Interleukin-2 - metabolism

Spleen - immunology

Receptors, Antigen, T-Cell - metabolism

Proline - metabolism

Protein-Tyrosine Kinases - metabolism

CD4-Positive T-Lymphocytes - metabolism

Hypersensitivity - immunology

Th2 Cells - immunology

Th2 Cells - metabolism

Protein-Tyrosine Kinases - immunology

CD4-Positive T-Lymphocytes - immunology

Animals

Cyclophilin A - immunology

Hypersensitivity - genetics

Protein Conformation

Receptors, Antigen, T-Cell - immunology

Thymus Gland - immunology

Cyclophilin A - genetics

Mice

Details

Title: Subtitle: Cyclophilin A regulates TCR signal strength in CD4+ T cells via a proline-directed conformational switch in Itk
Creators: John Colgan - Department of Microbiology, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, New York 10032, USA
Mohammed Asmal
Martha Neagu
Bin Yu
Jason Schneidkraut
Youngnam Lee
Elena Sokolskaja
Amy Andreotti
Jeremy Luban
Resource Type: Journal article
Publication Details: Immunity (Cambridge, Mass.), Vol.21(2), pp.189-201
Publisher: United States
DOI: 10.1016/j.immuni.2004.07.005
PMID: 15308100
ISSN: 1074-7613
eISSN: 1097-4180
Grant note: R01 AI036199 / NIAID NIH HHS AI 36199 / NIAID NIH HHS
Language: English
Date published: 08/2004
Academic Unit: Anatomy and Cell Biology; Immunology; Internal Medicine
Record Identifier: 9984025401202771

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