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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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Cre/PLCγ1fl/− mice develop inflammatory/autoimmune disease. (A) Cre/PLCγ1fl/− mice were smaller than littermate control mice. A pair of 6-wk-old littermates is shown. (B) PLCγ1 deficiency reduced weight gain in Cre/PLCγ1fl/− mice. Each point represents the mean weight of 7 to 14 female mice. *: P < 0.05. (C) Infiltration of inflammatory cells in the skin and ear (H&E, x200) of Cre/PLCγ1fl/− mice. Bar, 100 µm. (D) Infiltration of CD3+ T cells in the skin and ear (x200) of Cre/PLCγ1fl/− mice. The slides were analyzed by immunohistochemistry and examined by Nikon Eclipse E600. Bar, 100 µm. (E) Levels of α-double-stranded DNA antibodies and antinuclear antibodies in the serum of symptomatic Cre/PLCγ1fl/− mice compared with the indicated control mice.
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fig4: Cre/PLCγ1fl/− mice develop inflammatory/autoimmune disease. (A) Cre/PLCγ1fl/− mice were smaller than littermate control mice. A pair of 6-wk-old littermates is shown. (B) PLCγ1 deficiency reduced weight gain in Cre/PLCγ1fl/− mice. Each point represents the mean weight of 7 to 14 female mice. *: P < 0.05. (C) Infiltration of inflammatory cells in the skin and ear (H&E, x200) of Cre/PLCγ1fl/− mice. Bar, 100 µm. (D) Infiltration of CD3+ T cells in the skin and ear (x200) of Cre/PLCγ1fl/− mice. The slides were analyzed by immunohistochemistry and examined by Nikon Eclipse E600. Bar, 100 µm. (E) Levels of α-double-stranded DNA antibodies and antinuclear antibodies in the serum of symptomatic Cre/PLCγ1fl/− mice compared with the indicated control mice.

Mentions: From 2–3 wk of age, most Cre/PLCγ1fl/− mice were apparently runt (Fig. 4 A), with reduced weight in both male and female mice compared with littermate control mice (Fig. 4 B and not depicted). One third of Cre/PLCγ1fl/− mice developed variable visible symptoms, including alopecia, dermatitis, and rectal prolapse (symptomatic mice), with the latter two symptoms more frequent. Whereas none of the littermate control mice exhibited significant histological abnormalities, a majority of symptomatic Cre/PLCγ1fl/− mice showed infiltration of mononuclear cells into variable tissues, particularly skin and ear (Fig. 4 C). Although Cre/PLCγ1fl/− mice were severely T cell lymphopenic, the skin and ear were infiltrated by CD3+ T cells, which was not observed in the corresponding areas of the littermate control mice (Fig. 4 D). Serum anti–double-stranded DNA antibodies were significantly higher in symptomatic Cre/PLCγ1fl/− relative to nonsymptomatic Cre/PLCγ1fl/− or control mice (Fig. 4 E). Nevertheless, serum antinuclear antibodies were comparable (Fig. 4 E). The experimental mice analyzed were backcrossed with C57BL/6 mice for three generations. We have since determined that Cre/PLCγ1fl/− mice backcrossed with C57BL/6 mice for eight generations displayed the same phenotypes (unpublished data). Although we cannot entirely exclude background gene effects, we can conclude that the inflammatory/autoimmune syndrome in Cre/PLCγ1fl/− mice is attributable to PLCγ1 deficiency.


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)

Cre/PLCγ1fl/− mice develop inflammatory/autoimmune disease. (A) Cre/PLCγ1fl/− mice were smaller than littermate control mice. A pair of 6-wk-old littermates is shown. (B) PLCγ1 deficiency reduced weight gain in Cre/PLCγ1fl/− mice. Each point represents the mean weight of 7 to 14 female mice. *: P < 0.05. (C) Infiltration of inflammatory cells in the skin and ear (H&E, x200) of Cre/PLCγ1fl/− mice. Bar, 100 µm. (D) Infiltration of CD3+ T cells in the skin and ear (x200) of Cre/PLCγ1fl/− mice. The slides were analyzed by immunohistochemistry and examined by Nikon Eclipse E600. Bar, 100 µm. (E) Levels of α-double-stranded DNA antibodies and antinuclear antibodies in the serum of symptomatic Cre/PLCγ1fl/− mice compared with the indicated control mice.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig4: Cre/PLCγ1fl/− mice develop inflammatory/autoimmune disease. (A) Cre/PLCγ1fl/− mice were smaller than littermate control mice. A pair of 6-wk-old littermates is shown. (B) PLCγ1 deficiency reduced weight gain in Cre/PLCγ1fl/− mice. Each point represents the mean weight of 7 to 14 female mice. *: P < 0.05. (C) Infiltration of inflammatory cells in the skin and ear (H&E, x200) of Cre/PLCγ1fl/− mice. Bar, 100 µm. (D) Infiltration of CD3+ T cells in the skin and ear (x200) of Cre/PLCγ1fl/− mice. The slides were analyzed by immunohistochemistry and examined by Nikon Eclipse E600. Bar, 100 µm. (E) Levels of α-double-stranded DNA antibodies and antinuclear antibodies in the serum of symptomatic Cre/PLCγ1fl/− mice compared with the indicated control mice.
Mentions: From 2–3 wk of age, most Cre/PLCγ1fl/− mice were apparently runt (Fig. 4 A), with reduced weight in both male and female mice compared with littermate control mice (Fig. 4 B and not depicted). One third of Cre/PLCγ1fl/− mice developed variable visible symptoms, including alopecia, dermatitis, and rectal prolapse (symptomatic mice), with the latter two symptoms more frequent. Whereas none of the littermate control mice exhibited significant histological abnormalities, a majority of symptomatic Cre/PLCγ1fl/− mice showed infiltration of mononuclear cells into variable tissues, particularly skin and ear (Fig. 4 C). Although Cre/PLCγ1fl/− mice were severely T cell lymphopenic, the skin and ear were infiltrated by CD3+ T cells, which was not observed in the corresponding areas of the littermate control mice (Fig. 4 D). Serum anti–double-stranded DNA antibodies were significantly higher in symptomatic Cre/PLCγ1fl/− relative to nonsymptomatic Cre/PLCγ1fl/− or control mice (Fig. 4 E). Nevertheless, serum antinuclear antibodies were comparable (Fig. 4 E). The experimental mice analyzed were backcrossed with C57BL/6 mice for three generations. We have since determined that Cre/PLCγ1fl/− mice backcrossed with C57BL/6 mice for eight generations displayed the same phenotypes (unpublished data). Although we cannot entirely exclude background gene effects, we can conclude that the inflammatory/autoimmune syndrome in Cre/PLCγ1fl/− mice is attributable to PLCγ1 deficiency.

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