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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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Total cellularity and percentages of B cell populations in the  LNs, spleen, and BM of TC-PTP–deficient mice. Total cellularity on different days after birth from the (A) LNs, (B) spleen, and (C) BM. Data are  presented as the mean of 3–6 mice/group. Pre-B (B220+sIgM−) and mature B cell (B220+sIgM+) populations were determined by two-color  flow cytometry. Each column and row of FACS® profiles represents the  different groups (+/+, +/−, −/−) and different days after birth (D7,  D13, and D21), respectively. Numbers in the upper quadrants of each  FACS® profile represent the percentage of the population from the (D)  LNs, (E) spleen, and (F) BM.
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Figure 2: Total cellularity and percentages of B cell populations in the LNs, spleen, and BM of TC-PTP–deficient mice. Total cellularity on different days after birth from the (A) LNs, (B) spleen, and (C) BM. Data are presented as the mean of 3–6 mice/group. Pre-B (B220+sIgM−) and mature B cell (B220+sIgM+) populations were determined by two-color flow cytometry. Each column and row of FACS® profiles represents the different groups (+/+, +/−, −/−) and different days after birth (D7, D13, and D21), respectively. Numbers in the upper quadrants of each FACS® profile represent the percentage of the population from the (D) LNs, (E) spleen, and (F) BM.

Mentions: To further investigate the phenotype of TC-PTP −/− mice, animals were killed at different days after birth. Gross anatomical observations indicated a striking splenomegaly and lymphadenopathy (data not shown) in mutant mice in the third week of life. The LNs of these mice showed loss of follicular demarcation due to hyperplasia of the follicles as a result of increased number of immunoblasts (data not shown). Hematocrit level of mutant mice decreased with increasing age, leading to severe anemia by day 21. Since the percentage of mature B cells was markedly increased in the LNs (Fig. 2 D), we tested the possibility that autoantibodies against erythrocytes were being produced and could therefore cause severe anemia. Using both flow cytometry and the Coomb's test (35), we failed to detect IgM autoantibodies in the circulation (data not shown). Histological analysis showed that, in the spleen of some TC-PTP −/− mice, the red pulp area was expanded (data not shown), consistent with increased sequestration of RBCs. These results suggest that the spleen of TC-PTP −/− mice could not compensate for the defective BM erythropoiesis leading to severe anemia that could contribute to the morbidity and mortality.


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)

Total cellularity and percentages of B cell populations in the  LNs, spleen, and BM of TC-PTP–deficient mice. Total cellularity on different days after birth from the (A) LNs, (B) spleen, and (C) BM. Data are  presented as the mean of 3–6 mice/group. Pre-B (B220+sIgM−) and mature B cell (B220+sIgM+) populations were determined by two-color  flow cytometry. Each column and row of FACS® profiles represents the  different groups (+/+, +/−, −/−) and different days after birth (D7,  D13, and D21), respectively. Numbers in the upper quadrants of each  FACS® profile represent the percentage of the population from the (D)  LNs, (E) spleen, and (F) BM.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199020&req=5

Figure 2: Total cellularity and percentages of B cell populations in the LNs, spleen, and BM of TC-PTP–deficient mice. Total cellularity on different days after birth from the (A) LNs, (B) spleen, and (C) BM. Data are presented as the mean of 3–6 mice/group. Pre-B (B220+sIgM−) and mature B cell (B220+sIgM+) populations were determined by two-color flow cytometry. Each column and row of FACS® profiles represents the different groups (+/+, +/−, −/−) and different days after birth (D7, D13, and D21), respectively. Numbers in the upper quadrants of each FACS® profile represent the percentage of the population from the (D) LNs, (E) spleen, and (F) BM.
Mentions: To further investigate the phenotype of TC-PTP −/− mice, animals were killed at different days after birth. Gross anatomical observations indicated a striking splenomegaly and lymphadenopathy (data not shown) in mutant mice in the third week of life. The LNs of these mice showed loss of follicular demarcation due to hyperplasia of the follicles as a result of increased number of immunoblasts (data not shown). Hematocrit level of mutant mice decreased with increasing age, leading to severe anemia by day 21. Since the percentage of mature B cells was markedly increased in the LNs (Fig. 2 D), we tested the possibility that autoantibodies against erythrocytes were being produced and could therefore cause severe anemia. Using both flow cytometry and the Coomb's test (35), we failed to detect IgM autoantibodies in the circulation (data not shown). Histological analysis showed that, in the spleen of some TC-PTP −/− mice, the red pulp area was expanded (data not shown), consistent with increased sequestration of RBCs. These results suggest that the spleen of TC-PTP −/− mice could not compensate for the defective BM erythropoiesis leading to severe anemia that could contribute to the morbidity and mortality.

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