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Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice.

You-Ten KE, Muise ES, Itié A, Michaliszyn E, Wagner J, Jothy S, Lapp WS, Tremblay ML - J. Exp. Med. (1997)

Bottom Line: However, myeloid and macrophage development in the BM and T cell development in the thymus were not significantly affected.BM transplantation experiments showed that hematopoietic failure in TC-PTP -/- animals was not due to a stem cell defect, but rather to a stromal cell deficiency.This study demonstrates that TC-PTP plays a significant role in both hematopoiesis and immune function.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6.

ABSTRACT
The T cell protein tyrosine phosphatase (TC-PTP) is one of the most abundant mammalian tyrosine phosphatases in hematopoietic cells; however, its role in hematopoietic cell function remains unknown. In this report, we investigated the physiological function(s) of TC-PTP by generating TC-PTP-deficient mutant mice. The three genotypes (+/+, +/-, -/-) showed mendelian segregation at birth (1:2:1) demonstrating that the absence of TC-PTP was not lethal in utero, but all homozygous mutant mice died by 3-5 wk of age, displaying runting, splenomegaly, and lymphadenopathy. Homozygous mice exhibited specific defects in bone marrow (BM), B cell lymphopoiesis, and erythropoiesis, as well as impaired T and B cell functions. However, myeloid and macrophage development in the BM and T cell development in the thymus were not significantly affected. BM transplantation experiments showed that hematopoietic failure in TC-PTP -/- animals was not due to a stem cell defect, but rather to a stromal cell deficiency. This study demonstrates that TC-PTP plays a significant role in both hematopoiesis and immune function.

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Immune function and hematocrit of irradiated wt recipients  rescued with wt or TC-PTP–deficient BM. (A) Immune function of irradiated wt recipients reconstituted with TC-PTP wt or −/− BM. Immune function was assessed by the ability of splenic cells to proliferate in  response to Con A and LPS. Data represents the mean ± SE of 3–6 mice/ group. (B) Hematocrit level of irradiated wt recipients rescued with TC-PTP −/− BM. Data are presented as the mean ± SE of 3 mice/group.
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Figure 4: Immune function and hematocrit of irradiated wt recipients rescued with wt or TC-PTP–deficient BM. (A) Immune function of irradiated wt recipients reconstituted with TC-PTP wt or −/− BM. Immune function was assessed by the ability of splenic cells to proliferate in response to Con A and LPS. Data represents the mean ± SE of 3–6 mice/ group. (B) Hematocrit level of irradiated wt recipients rescued with TC-PTP −/− BM. Data are presented as the mean ± SE of 3 mice/group.

Mentions: To further examine the ability of TC-PTP −/− BM to reconstitute irradiated wt recipients, the BM transplanted mice were killed 2 mo after reconstitution. B and T cell populations expressed the neo gene, confirming that the lymphoid cells population were derived from the injected PTP −/− BM (data not shown). Gross observation revealed that the spleen and LNs of these recipients were not enlarged and were similar in size to the control group. Flow cytometry showed that, unlike the nonreconstituted, nonirradiated TC-PTP −/− mice (Table 1), the thymus of wt recipients reconstituted with TC-PTP −/− BM did not undergo atrophy (Table 3), and B cell production in the BM of the rescued recipients was similar to that of control irradiated wt recipients reconstituted with wt BM (Table 3). Moreover, the hematocrit and the number of pre-B and mature B cells in the spleen and LNs of the recipients reconstituted with TC-PTP −/− BM were also similar to the control groups (Fig. 4 B and Table 3). Although T and B cells developed normally in recipients rescued with TC-PTP −/− BM, T and B cell proliferative response to mitogens remained defective suggesting that TC-PTP is important for the development of functional competence of T and B cells (Fig. 4 A). Together, the above studies indicate that BM of TC-PTP −/− mice contains stem cells capable of differentiating and maturing in a normal BM microenvironment. In support of this hypothesis, histological analysis of the BM microenvironment demonstrated that the number of stromal cells in the BM of TC-PTP −/− mice was reduced when compared to wt and heterozygous animals (Fig. 5). Thus, the TC-PTP −/− mutation could lead to a quantitative and/or qualitative alteration in BM microenvironmental function in these mice.


Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice.

You-Ten KE, Muise ES, Itié A, Michaliszyn E, Wagner J, Jothy S, Lapp WS, Tremblay ML - J. Exp. Med. (1997)

Immune function and hematocrit of irradiated wt recipients  rescued with wt or TC-PTP–deficient BM. (A) Immune function of irradiated wt recipients reconstituted with TC-PTP wt or −/− BM. Immune function was assessed by the ability of splenic cells to proliferate in  response to Con A and LPS. Data represents the mean ± SE of 3–6 mice/ group. (B) Hematocrit level of irradiated wt recipients rescued with TC-PTP −/− BM. Data are presented as the mean ± SE of 3 mice/group.
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Related In: Results  -  Collection

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Figure 4: Immune function and hematocrit of irradiated wt recipients rescued with wt or TC-PTP–deficient BM. (A) Immune function of irradiated wt recipients reconstituted with TC-PTP wt or −/− BM. Immune function was assessed by the ability of splenic cells to proliferate in response to Con A and LPS. Data represents the mean ± SE of 3–6 mice/ group. (B) Hematocrit level of irradiated wt recipients rescued with TC-PTP −/− BM. Data are presented as the mean ± SE of 3 mice/group.
Mentions: To further examine the ability of TC-PTP −/− BM to reconstitute irradiated wt recipients, the BM transplanted mice were killed 2 mo after reconstitution. B and T cell populations expressed the neo gene, confirming that the lymphoid cells population were derived from the injected PTP −/− BM (data not shown). Gross observation revealed that the spleen and LNs of these recipients were not enlarged and were similar in size to the control group. Flow cytometry showed that, unlike the nonreconstituted, nonirradiated TC-PTP −/− mice (Table 1), the thymus of wt recipients reconstituted with TC-PTP −/− BM did not undergo atrophy (Table 3), and B cell production in the BM of the rescued recipients was similar to that of control irradiated wt recipients reconstituted with wt BM (Table 3). Moreover, the hematocrit and the number of pre-B and mature B cells in the spleen and LNs of the recipients reconstituted with TC-PTP −/− BM were also similar to the control groups (Fig. 4 B and Table 3). Although T and B cells developed normally in recipients rescued with TC-PTP −/− BM, T and B cell proliferative response to mitogens remained defective suggesting that TC-PTP is important for the development of functional competence of T and B cells (Fig. 4 A). Together, the above studies indicate that BM of TC-PTP −/− mice contains stem cells capable of differentiating and maturing in a normal BM microenvironment. In support of this hypothesis, histological analysis of the BM microenvironment demonstrated that the number of stromal cells in the BM of TC-PTP −/− mice was reduced when compared to wt and heterozygous animals (Fig. 5). Thus, the TC-PTP −/− mutation could lead to a quantitative and/or qualitative alteration in BM microenvironmental function in these mice.

Bottom Line: However, myeloid and macrophage development in the BM and T cell development in the thymus were not significantly affected.BM transplantation experiments showed that hematopoietic failure in TC-PTP -/- animals was not due to a stem cell defect, but rather to a stromal cell deficiency.This study demonstrates that TC-PTP plays a significant role in both hematopoiesis and immune function.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6.

ABSTRACT
The T cell protein tyrosine phosphatase (TC-PTP) is one of the most abundant mammalian tyrosine phosphatases in hematopoietic cells; however, its role in hematopoietic cell function remains unknown. In this report, we investigated the physiological function(s) of TC-PTP by generating TC-PTP-deficient mutant mice. The three genotypes (+/+, +/-, -/-) showed mendelian segregation at birth (1:2:1) demonstrating that the absence of TC-PTP was not lethal in utero, but all homozygous mutant mice died by 3-5 wk of age, displaying runting, splenomegaly, and lymphadenopathy. Homozygous mice exhibited specific defects in bone marrow (BM), B cell lymphopoiesis, and erythropoiesis, as well as impaired T and B cell functions. However, myeloid and macrophage development in the BM and T cell development in the thymus were not significantly affected. BM transplantation experiments showed that hematopoietic failure in TC-PTP -/- animals was not due to a stem cell defect, but rather to a stromal cell deficiency. This study demonstrates that TC-PTP plays a significant role in both hematopoiesis and immune function.

Show MeSH
Related in: MedlinePlus