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The FERM and PDZ domain-containing protein tyrosine phosphatases, PTPN4 and PTPN3, are both dispensable for T cell receptor signal transduction.

Bauler TJ, Hendriks WJ, King PD - PLoS ONE (2008)

Bottom Line: PTPN13 is another FERM and PDZ domain-containing non-receptor PTP that is distantly-related to PTPN3 and PTPN4 and which has been shown to function as a negative-regulator of T helper-1 (Th1) and Th2 differentiation.Furthermore, T cell differentiation along the Th1, Th2 and Th17 lineages was largely unaffected in triple-mutants.We conclude that PTPN3 and PTPN4 are dispensable for TCR signal transduction.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.

ABSTRACT
PTPN3 and PTPN4 are two closely-related non-receptor protein tyrosine phosphatases (PTP) that, in addition to a PTP domain, contain FERM (Band 4.1, Ezrin, Radixin, and Moesin) and PDZ (PSD-95, Dlg, ZO-1) domains. Both PTP have been implicated as negative-regulators of early signal transduction through the T cell antigen receptor (TCR), acting to dephosphorylate the TCRzeta chain, a component of the TCR complex. Previously, we reported upon the production and characterization of PTPN3-deficient mice which show normal TCR signal transduction and T cell function. To address if the lack of a T cell phenotype in PTPN3-deficient mice can be explained by functional redundancy of PTPN3 with PTPN4, we generated PTPN4-deficient and PTPN4/PTPN3 double-deficient mice. As in PTPN3 mutants, T cell development and homeostasis and TCR-induced cytokine synthesis and proliferation were found to be normal in PTPN4-deficient and PTPN4/PTPN3 double-deficient mice. PTPN13 is another FERM and PDZ domain-containing non-receptor PTP that is distantly-related to PTPN3 and PTPN4 and which has been shown to function as a negative-regulator of T helper-1 (Th1) and Th2 differentiation. Therefore, to determine if PTPN13 might compensate for the loss of PTPN3 and PTPN4 in T cells, we generated mice that lack functional forms of all three PTP. T cells from triple-mutant mice developed normally and showed normal cytokine secretion and proliferative responses to TCR stimulation. Furthermore, T cell differentiation along the Th1, Th2 and Th17 lineages was largely unaffected in triple-mutants. We conclude that PTPN3 and PTPN4 are dispensable for TCR signal transduction.

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T cell cytokine synthesis and proliferation in PTPN4/PTPN3 double-deficient mice.A) LN T cells were stimulated with the indicated concentrations of CD3 antibody and 0.75 µg/mL CD28 antibody. Concentrations of cytokines in supernatants were determined as in Figure 2. Each bar represents the mean plus one standard deviation of triplicate determinations from one mouse. Differences between mice are not statistically significant (Student's T-test). Data are representative of six repeat experiments. B) Splenic T cells were labeled with CFSE and stimulated with 0.1 µg/mL CD3 antibody and 0.75 µg/mL CD28 antibody. After 72 h, CFSE dye intensity was measured by flow cytometry. The percentage of live cells that have undergone the indicated number of cell divisions is shown. Data are representative of three repeat experiments.
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pone-0004014-g004: T cell cytokine synthesis and proliferation in PTPN4/PTPN3 double-deficient mice.A) LN T cells were stimulated with the indicated concentrations of CD3 antibody and 0.75 µg/mL CD28 antibody. Concentrations of cytokines in supernatants were determined as in Figure 2. Each bar represents the mean plus one standard deviation of triplicate determinations from one mouse. Differences between mice are not statistically significant (Student's T-test). Data are representative of six repeat experiments. B) Splenic T cells were labeled with CFSE and stimulated with 0.1 µg/mL CD3 antibody and 0.75 µg/mL CD28 antibody. After 72 h, CFSE dye intensity was measured by flow cytometry. The percentage of live cells that have undergone the indicated number of cell divisions is shown. Data are representative of three repeat experiments.

Mentions: To examine the influence of loss of expression of PTPN4 and PTPN3 upon T cell function, we examined both T cell cytokine synthesis and T cell proliferation in PTPN4/PTPN3 double-deficient mice. Synthesis of IL-2, IFN-γ and IL-4 in response to CD3/CD28 antibody stimulation was determined as before (Figure 4A). As shown, T cells from PTPN4/PTPN3 double-deficient mice secreted similar quantities of these cytokines in these assays as T cells from control mice. To assess division, T cells were labeled with CFSE and dilution of CFSE was determined 72 h post-CD3/CD28 stimulation (Figure 4B). These analyses revealed that PTPN4/PTPN3 double-deficient T cells proliferate comparably to control T cells in vitro.


The FERM and PDZ domain-containing protein tyrosine phosphatases, PTPN4 and PTPN3, are both dispensable for T cell receptor signal transduction.

Bauler TJ, Hendriks WJ, King PD - PLoS ONE (2008)

T cell cytokine synthesis and proliferation in PTPN4/PTPN3 double-deficient mice.A) LN T cells were stimulated with the indicated concentrations of CD3 antibody and 0.75 µg/mL CD28 antibody. Concentrations of cytokines in supernatants were determined as in Figure 2. Each bar represents the mean plus one standard deviation of triplicate determinations from one mouse. Differences between mice are not statistically significant (Student's T-test). Data are representative of six repeat experiments. B) Splenic T cells were labeled with CFSE and stimulated with 0.1 µg/mL CD3 antibody and 0.75 µg/mL CD28 antibody. After 72 h, CFSE dye intensity was measured by flow cytometry. The percentage of live cells that have undergone the indicated number of cell divisions is shown. Data are representative of three repeat experiments.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2602985&req=5

pone-0004014-g004: T cell cytokine synthesis and proliferation in PTPN4/PTPN3 double-deficient mice.A) LN T cells were stimulated with the indicated concentrations of CD3 antibody and 0.75 µg/mL CD28 antibody. Concentrations of cytokines in supernatants were determined as in Figure 2. Each bar represents the mean plus one standard deviation of triplicate determinations from one mouse. Differences between mice are not statistically significant (Student's T-test). Data are representative of six repeat experiments. B) Splenic T cells were labeled with CFSE and stimulated with 0.1 µg/mL CD3 antibody and 0.75 µg/mL CD28 antibody. After 72 h, CFSE dye intensity was measured by flow cytometry. The percentage of live cells that have undergone the indicated number of cell divisions is shown. Data are representative of three repeat experiments.
Mentions: To examine the influence of loss of expression of PTPN4 and PTPN3 upon T cell function, we examined both T cell cytokine synthesis and T cell proliferation in PTPN4/PTPN3 double-deficient mice. Synthesis of IL-2, IFN-γ and IL-4 in response to CD3/CD28 antibody stimulation was determined as before (Figure 4A). As shown, T cells from PTPN4/PTPN3 double-deficient mice secreted similar quantities of these cytokines in these assays as T cells from control mice. To assess division, T cells were labeled with CFSE and dilution of CFSE was determined 72 h post-CD3/CD28 stimulation (Figure 4B). These analyses revealed that PTPN4/PTPN3 double-deficient T cells proliferate comparably to control T cells in vitro.

Bottom Line: PTPN13 is another FERM and PDZ domain-containing non-receptor PTP that is distantly-related to PTPN3 and PTPN4 and which has been shown to function as a negative-regulator of T helper-1 (Th1) and Th2 differentiation.Furthermore, T cell differentiation along the Th1, Th2 and Th17 lineages was largely unaffected in triple-mutants.We conclude that PTPN3 and PTPN4 are dispensable for TCR signal transduction.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.

ABSTRACT
PTPN3 and PTPN4 are two closely-related non-receptor protein tyrosine phosphatases (PTP) that, in addition to a PTP domain, contain FERM (Band 4.1, Ezrin, Radixin, and Moesin) and PDZ (PSD-95, Dlg, ZO-1) domains. Both PTP have been implicated as negative-regulators of early signal transduction through the T cell antigen receptor (TCR), acting to dephosphorylate the TCRzeta chain, a component of the TCR complex. Previously, we reported upon the production and characterization of PTPN3-deficient mice which show normal TCR signal transduction and T cell function. To address if the lack of a T cell phenotype in PTPN3-deficient mice can be explained by functional redundancy of PTPN3 with PTPN4, we generated PTPN4-deficient and PTPN4/PTPN3 double-deficient mice. As in PTPN3 mutants, T cell development and homeostasis and TCR-induced cytokine synthesis and proliferation were found to be normal in PTPN4-deficient and PTPN4/PTPN3 double-deficient mice. PTPN13 is another FERM and PDZ domain-containing non-receptor PTP that is distantly-related to PTPN3 and PTPN4 and which has been shown to function as a negative-regulator of T helper-1 (Th1) and Th2 differentiation. Therefore, to determine if PTPN13 might compensate for the loss of PTPN3 and PTPN4 in T cells, we generated mice that lack functional forms of all three PTP. T cells from triple-mutant mice developed normally and showed normal cytokine secretion and proliferative responses to TCR stimulation. Furthermore, T cell differentiation along the Th1, Th2 and Th17 lineages was largely unaffected in triple-mutants. We conclude that PTPN3 and PTPN4 are dispensable for TCR signal transduction.

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