Open AccessCoordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis
Author(s) -
Fukun Guo,
David A. Hildeman,
Pulak Tripathi,
Chinavenmeni S. Velu,
H. Leighton Grimes,
Yi Zheng
Publication year - 2010
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1010249107
Subject(s) - cdc42 , microbiology and biotechnology , biology , t cell receptor , t cell , signal transduction , homeostasis , cell growth , immune system , immunology , biochemistry
T-cell homeostasis is essential for normal functioning of the immune system. IL-7 receptor (IL-7R) and T-cell receptor (TCR) signaling are pivotal for T-cell homeostatic regulation. The detailed mechanisms regulating T-cell homeostasis and how IL-7R and TCR signaling are coordinated are largely unknown. Here we demonstrate that T cell-specific deletion ofcell-division cycle 42 (Cdc42 ) GTPase causes a profound loss of mature T cells. Deletion ofCdc42 leads to a markedly increased expression of growth factor independence-1 (Gfi-1) and represses expression of IL-7Rα. In the absence ofCdc42 , aberrant ERK1/2 MAP kinase activity results in enhanced, TCR-mediated T-cell proliferation. In vivo reconstitution of effector-binding–defective Cdc42 mutants and the effector p21 protein-activated kinase 1 (PAK1) intoCdc42 -deficient T cells showed that PAK1 is both necessary and sufficient for Cdc42-regulated T-cell homeostasis. Thus, T-cell homeostasis is maintained through a concerted regulation of Gfi-1–IL-7R–controlled cytokine responsiveness and ERK-mediated TCR signaling strength by the Cdc42-PAK1 signaling axis.