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Phospholipase C{gamma}1 is essential for T cell development, activation, and tolerance.

Fu G, Chen Y, Yu M, Podd A, Schuman J, He Y, Di L, Yassai M, Haribhai D, North PE, Gorski J, Williams CB, Wang D, Wen R - J. Exp. Med. (2010)

Bottom Line: Phospholipase Cgamma1 (PLCgamma1) is an important signaling effector of T cell receptor (TCR).We demonstrate that PLCgamma1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-kappaB.Therefore, PLCgamma1 is essential for T cell development, activation, and tolerance.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA.

ABSTRACT
Phospholipase Cgamma1 (PLCgamma1) is an important signaling effector of T cell receptor (TCR). To investigate the role of PLCgamma1 in T cell biology, we generated and examined mice with T cell-specific deletion of PLCgamma1. We demonstrate that PLCgamma1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-kappaB. Importantly, PLCgamma1 deficiency impairs the development and function of FoxP3(+) regulatory T cells, causing inflammatory/autoimmune symptoms. Therefore, PLCgamma1 is essential for T cell development, activation, and tolerance.

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PLCγ1 deficiency impairs T reg cell development and function. (A) PLCγ1-deficient T cells display activated phenotype. Data are representative of four pairs of mice. (B) Percentages of FoxP3+ T reg cells in total and CD4-gated lymphocytes in the thymus, spleen, and lymph node cells. Data represent five pairs of mice. (C) CD4+FoxP3+ cell numbers were reduced in thymus and spleen of Cre/PLCγ1fl/− mice. Data represent five pairs of mice. (D) PLCγ1 deficiency impairs the inhibitory functions of T reg cells. Error bars represent the standard deviation of triplicate measurements of each data point. *: P < 0.05, **: P < 0.01. Data are representative of two independent experiments. (E) WT T reg cell reconstitution restores normal weight gain in Cre/PLCγ1fl/− mice. Each point represents the mean weight of 7 to 14 female Cre/PLCγ1+/− mice or 6 female Cre/PLCγ1fl/− mice that received WT T reg cells. (F) WT T reg cell reconstitution restores high CD62L expression on PLCγ1-deficient T cells. Data represent three independent experiments.
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fig5: PLCγ1 deficiency impairs T reg cell development and function. (A) PLCγ1-deficient T cells display activated phenotype. Data are representative of four pairs of mice. (B) Percentages of FoxP3+ T reg cells in total and CD4-gated lymphocytes in the thymus, spleen, and lymph node cells. Data represent five pairs of mice. (C) CD4+FoxP3+ cell numbers were reduced in thymus and spleen of Cre/PLCγ1fl/− mice. Data represent five pairs of mice. (D) PLCγ1 deficiency impairs the inhibitory functions of T reg cells. Error bars represent the standard deviation of triplicate measurements of each data point. *: P < 0.05, **: P < 0.01. Data are representative of two independent experiments. (E) WT T reg cell reconstitution restores normal weight gain in Cre/PLCγ1fl/− mice. Each point represents the mean weight of 7 to 14 female Cre/PLCγ1+/− mice or 6 female Cre/PLCγ1fl/− mice that received WT T reg cells. (F) WT T reg cell reconstitution restores high CD62L expression on PLCγ1-deficient T cells. Data represent three independent experiments.

Mentions: T cells in Cre/YFP/PLCγ1fl/− mice showed activated phenotype, including larger cell sizes, decreased CD62L, and increased CD44 expression compared with those in Cre/YFP/PLCγ1+/− mice (Fig. 5 A). T cell lymphopenia and the activated phenotype of PLCγ1-deficient T cells were largely corrected in mice receiving Cre/YFP/PLCγ1fl/− and WT BM cells (Fig. S3). Thus, T cell lymphopenia may contribute to the activated T cell phenotype in PLCγ1-deficient mice. Alternatively, given that the symptoms of Cre/PLCγ1fl/− mice are reminiscent of mice deficient in FoxP3+ T reg cells (Fontenot et al., 2003; Hori et al., 2003; Khattri et al., 2003), the autoimmune phenotype may be consequent to impaired T reg cells. The percentage and absolute number of T reg cells were substantially reduced in thymus in Cre/PLCγ1fl/− relative to Cre/PLCγ1+/− mice (Fig. 5, B and C). Although T reg cell percentage was reduced in lymphocytes in the spleen and lymph nodes of Cre/PLCγ1fl/− relative to Cre/PLCγ1+/− mice, it was substantially increased in CD4+ T cells (Fig. 5 B). Nevertheless, T reg cell number was dramatically reduced in the spleen from Cre/PLCγ1fl/− relative to Cre/PLCγ1+/− mice (Fig. 5 C). We performed suppression assays to determine T reg cell suppressive functions. Compared with those from Cre/YFP/PLCγ1+/− mice, YFP+ T reg cells from Cre/YFP/PLCγ1fl/− mice had reduced ability to suppress naive T cell proliferation (Fig. 5 D). Furthermore, we transferred purified WT T reg cells into 10 10-d-old Cre/YFP/PLCγ1fl/− mice to determine whether impaired T reg cells contributed to the disease phenotype in PLCγ1-deficient mice. None of them developed symptoms such as alopecia, dermatitis, and rectal prolapse. These mice gained weight at a rate similar to WT mice (Fig. 5 E). WT T reg cells also partially corrected the activated phenotype of Cre/YFP/PLCγ1fl/− T cells, as CD62L expression was increased (Fig. 5 F). Collectively, PLCγ1 deficiency impaired T reg cell development and functions, which may contribute to the inflammatory/autoimmune disease in the PLCγ1-deficient mice.


Phospholipase C{gamma}1 is essential for T cell development, activation, and tolerance.

Fu G, Chen Y, Yu M, Podd A, Schuman J, He Y, Di L, Yassai M, Haribhai D, North PE, Gorski J, Williams CB, Wang D, Wen R - J. Exp. Med. (2010)

PLCγ1 deficiency impairs T reg cell development and function. (A) PLCγ1-deficient T cells display activated phenotype. Data are representative of four pairs of mice. (B) Percentages of FoxP3+ T reg cells in total and CD4-gated lymphocytes in the thymus, spleen, and lymph node cells. Data represent five pairs of mice. (C) CD4+FoxP3+ cell numbers were reduced in thymus and spleen of Cre/PLCγ1fl/− mice. Data represent five pairs of mice. (D) PLCγ1 deficiency impairs the inhibitory functions of T reg cells. Error bars represent the standard deviation of triplicate measurements of each data point. *: P < 0.05, **: P < 0.01. Data are representative of two independent experiments. (E) WT T reg cell reconstitution restores normal weight gain in Cre/PLCγ1fl/− mice. Each point represents the mean weight of 7 to 14 female Cre/PLCγ1+/− mice or 6 female Cre/PLCγ1fl/− mice that received WT T reg cells. (F) WT T reg cell reconstitution restores high CD62L expression on PLCγ1-deficient T cells. Data represent three independent experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2822604&req=5

fig5: PLCγ1 deficiency impairs T reg cell development and function. (A) PLCγ1-deficient T cells display activated phenotype. Data are representative of four pairs of mice. (B) Percentages of FoxP3+ T reg cells in total and CD4-gated lymphocytes in the thymus, spleen, and lymph node cells. Data represent five pairs of mice. (C) CD4+FoxP3+ cell numbers were reduced in thymus and spleen of Cre/PLCγ1fl/− mice. Data represent five pairs of mice. (D) PLCγ1 deficiency impairs the inhibitory functions of T reg cells. Error bars represent the standard deviation of triplicate measurements of each data point. *: P < 0.05, **: P < 0.01. Data are representative of two independent experiments. (E) WT T reg cell reconstitution restores normal weight gain in Cre/PLCγ1fl/− mice. Each point represents the mean weight of 7 to 14 female Cre/PLCγ1+/− mice or 6 female Cre/PLCγ1fl/− mice that received WT T reg cells. (F) WT T reg cell reconstitution restores high CD62L expression on PLCγ1-deficient T cells. Data represent three independent experiments.
Mentions: T cells in Cre/YFP/PLCγ1fl/− mice showed activated phenotype, including larger cell sizes, decreased CD62L, and increased CD44 expression compared with those in Cre/YFP/PLCγ1+/− mice (Fig. 5 A). T cell lymphopenia and the activated phenotype of PLCγ1-deficient T cells were largely corrected in mice receiving Cre/YFP/PLCγ1fl/− and WT BM cells (Fig. S3). Thus, T cell lymphopenia may contribute to the activated T cell phenotype in PLCγ1-deficient mice. Alternatively, given that the symptoms of Cre/PLCγ1fl/− mice are reminiscent of mice deficient in FoxP3+ T reg cells (Fontenot et al., 2003; Hori et al., 2003; Khattri et al., 2003), the autoimmune phenotype may be consequent to impaired T reg cells. The percentage and absolute number of T reg cells were substantially reduced in thymus in Cre/PLCγ1fl/− relative to Cre/PLCγ1+/− mice (Fig. 5, B and C). Although T reg cell percentage was reduced in lymphocytes in the spleen and lymph nodes of Cre/PLCγ1fl/− relative to Cre/PLCγ1+/− mice, it was substantially increased in CD4+ T cells (Fig. 5 B). Nevertheless, T reg cell number was dramatically reduced in the spleen from Cre/PLCγ1fl/− relative to Cre/PLCγ1+/− mice (Fig. 5 C). We performed suppression assays to determine T reg cell suppressive functions. Compared with those from Cre/YFP/PLCγ1+/− mice, YFP+ T reg cells from Cre/YFP/PLCγ1fl/− mice had reduced ability to suppress naive T cell proliferation (Fig. 5 D). Furthermore, we transferred purified WT T reg cells into 10 10-d-old Cre/YFP/PLCγ1fl/− mice to determine whether impaired T reg cells contributed to the disease phenotype in PLCγ1-deficient mice. None of them developed symptoms such as alopecia, dermatitis, and rectal prolapse. These mice gained weight at a rate similar to WT mice (Fig. 5 E). WT T reg cells also partially corrected the activated phenotype of Cre/YFP/PLCγ1fl/− T cells, as CD62L expression was increased (Fig. 5 F). Collectively, PLCγ1 deficiency impaired T reg cell development and functions, which may contribute to the inflammatory/autoimmune disease in the PLCγ1-deficient mice.

Bottom Line: Phospholipase Cgamma1 (PLCgamma1) is an important signaling effector of T cell receptor (TCR).We demonstrate that PLCgamma1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-kappaB.Therefore, PLCgamma1 is essential for T cell development, activation, and tolerance.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA.

ABSTRACT
Phospholipase Cgamma1 (PLCgamma1) is an important signaling effector of T cell receptor (TCR). To investigate the role of PLCgamma1 in T cell biology, we generated and examined mice with T cell-specific deletion of PLCgamma1. We demonstrate that PLCgamma1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-kappaB. Importantly, PLCgamma1 deficiency impairs the development and function of FoxP3(+) regulatory T cells, causing inflammatory/autoimmune symptoms. Therefore, PLCgamma1 is essential for T cell development, activation, and tolerance.

Show MeSH
Related in: MedlinePlus