SLAT regulates Th1 and Th2 inflammatory responses by controlling Ca2+/NFAT signaling
Stéphane Bécart, … , Michael Croft, Amnon Altman
Stéphane Bécart, … , Michael Croft, Amnon Altman
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2164-2175. https://doi.org/10.1172/JCI31640.
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Research Article Immunology

SLAT regulates Th1 and Th2 inflammatory responses by controlling Ca2+/NFAT signaling

Abstract

SWAP-70–like adapter of T cells (SLAT) is a novel guanine nucleotide exchange factor for Rho GTPases that is upregulated in Th2 cells, but whose physiological function is unclear. We show that SLAT–/– mice displayed a developmental defect at one of the earliest stages of thymocyte differentiation, the double-negative 1 (DN1) stage, leading to decreased peripheral T cell numbers. SLAT–/– peripheral CD4+ T cells demonstrated impaired TCR/CD28-induced proliferation and IL-2 production, which was rescued by the addition of exogenous IL-2. Importantly, SLAT–/– mice were grossly impaired in their ability to mount not only Th2, but also Th1-mediated lung inflammatory responses, as evidenced by reduced airway neutrophilia and eosinophilia, respectively. Levels of Th1 and Th2 cytokine in the lungs were also markedly reduced, paralleling the reduction in pulmonary inflammation. This defect in mounting Th1/Th2 responses, which was also evident in vitro, was traced to a severe reduction in Ca2+ mobilization from ER stores, which consequently led to defective TCR/CD28-induced translocation of nuclear factor of activated T cells 1/2 (NFATc1/2). Thus, SLAT is required for thymic DN1 cell expansion, T cell activation, and Th1 and Th2 inflammatory responses.

Authors

Stéphane Bécart, Céline Charvet, Ann J. Canonigo Balancio, Carl De Trez, Yoshihiko Tanaka, Wei Duan, Carl Ware, Michael Croft, Amnon Altman

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Figure 4

Defective activation of SLAT–/– CD4+ T cells.

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Defective activation of SLAT–/– CD4+ T cells. (A) Purifi...
(A) Purified peripheral CD4+ T cells from WT and SLAT–/– mice were stimulated with the indicated concentrations of plate-coated anti-CD3 plus soluble anti-CD28 mAbs for 48 hours. [3H]thymidine was added for the final 18 hours of culture, and proliferation was measured by tritium uptake. Proliferation of PMA (20 ng/ml) plus ionomycin–stimulated (500 ng/ml) T cells was also analyzed (right). iono, ionomycin. (B) CFSE-labeled purified CD4+ T cells from WT or SLAT–/– mice were left unstimulated or stimulated with anti-CD3 (5 μg/ml) plus anti-CD28 (2.5 μg/ml) mAbs or with PMA plus ionomycin for 72 hours. Cell division was determined by flow cytometry analysis (left panels). The percentage of cells with more than 2 divisions is shown (right panel). (C) Purified CD4+ T cells from WT or SLAT–/– mice were stimulated as in A, and IL-2 production was measured by an ELISA. (D) Purified CD4+ T cells from WT or SLAT–/– mice were stimulated with anti-CD3 (10 μg/ml) plus anti-CD28 (2.5 μg/ml) mAbs or PMA plus ionomycin in the presence or absence of exogenous IL-2 (100 U/ml), and proliferation was measured as in A. (E) Purified CD4+ T cells from WT and SLAT–/– mice were stimulated as in D for 16 hours and analyzed by flow cytometry for CD25 or CD69 expression. Results are expressed as mean ± SD. Statistical differences were determined as in Figure 2. **P < 0.01, #P < 0.001, WT versus SLAT–/– mice.