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Hematopoietic cell protein-tyrosine phosphatase-deficient motheaten mice exhibit T cell apoptosis defect
1Department of Medicine, the University of Alabama at Birmingham, AL 35294, USA.
Abstract:
We previously demonstrated that hematopoietic cell protein-tyrosine phosphatase is one of the molecules that can transduce Fas-mediated apoptosis signals in lymphoid cells. The present study analyzed the effect of defective Fas signaling on the T cell phenotype and apoptosis function in hematopoietic cell protein-tyrosine phosphatase-deficient motheaten mice. Viable motheaten (me(v)/me(v)) mice exhibited increased T cell proliferation and defective activation-induced apoptosis of Fas+ T cells in the lymph node, which was not ascribed to defective Fas ligand function. Furthermore, the Fas-mediated apoptosis defect in activated T cells from me(v)/me(v) mice was confirmed by their resistance to anti-Fas-induced apoptosis. No protein tyrosine dephosphorylation signal was delivered after anti-Fas cross-linking in the lymph node cells of me(v)/me(v) mice as revealed by 32Pi labeling of protein phosphatase substrates. The defective activation-induced apoptosis of Fas+ T cells in me(v)/me(v) mice led to lymphadenopathy with an accumulation of CD4- CD8- B220+ CD3+ T cells. Pneumonitis in me(v)/me(v) mice was associated with infiltration of cycling T cells detected by bromodeoxyuridine uptake in vivo. Thus, T cells from me(v)/me(v) mice are resistant to Fas-mediated apoptosis which results in lymphoproliferative disease and tissue infiltration.
Insights
Hematopoietic cell protein-tyrosine phosphatase deficiency impairs Fas-mediated apoptosis in T cells, leading to lymphoproliferative disease and tissue infiltration in mice.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Hematopoietic cell protein-tyrosine phosphatase (HCPTP) transduces Fas-mediated apoptosis signals in lymphoid cells.
- Defective Fas signaling impacts T cell phenotype and function.
Purpose of the Study:
- To analyze the effects of defective Fas signaling on T cell phenotype and apoptosis in HCPTP-deficient motheaten mice.
- To investigate the mechanism of Fas-mediated apoptosis resistance in these mice.
Main Methods:
- Analysis of T cell proliferation and apoptosis in viable motheaten (me(v)/me(v)) mice.
- Assessment of Fas ligand function.
- Confirmation of Fas-mediated apoptosis defect via anti-Fas-induced apoptosis assays.
- Evaluation of protein tyrosine dephosphorylation after anti-Fas cross-linking using 32Pi labeling.
- Characterization of T cell populations (CD4, CD8, B220, CD3) and cell cycling (bromodeoxyuridine uptake).
Main Results:
- me(v)/me(v) mice showed increased T cell proliferation and defective activation-induced apoptosis of Fas+ T cells.
- Resistance to anti-Fas-induced apoptosis was observed in activated T cells from me(v)/me(v) mice.
- No protein tyrosine dephosphorylation signal occurred after anti-Fas cross-linking in me(v)/me(v) lymph node cells.
- Defective apoptosis led to lymphadenopathy with accumulation of CD4- CD8- B220+ CD3+ T cells.
- Pneumonitis was associated with infiltration of cycling T cells.
Conclusions:
- T cells from me(v)/me(v) mice are resistant to Fas-mediated apoptosis.
- This resistance results in lymphoproliferative disease and tissue infiltration.
- HCPTP plays a crucial role in transducing Fas-mediated apoptosis signals in T cells.