Cyclophilin A regulates TCR signal strength in CD4+ T cells via a proline-directed conformational switch in Itk.
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.
Department of Microbiology, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, New York 10032, USA.
John
J
Colgan
Mohammed
M
Asmal
Martha
M
Neagu
Bin
B
Yu
Jason
J
Schneidkraut
Youngnam
Y
Lee
Elena
E
Sokolskaja
Amy
A
Andreotti
Jeremy
J
Luban
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D021984:Cyclophilin A / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D011392:Proline / Q000378:metabolism*; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology
D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011392:Proline; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; D021984:Cyclophilin A