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Thymic involution in viable motheaten (me(v)) mice is associated with a loss of intrathymic precursor activity
S M Hayes1, L D Shultz, D L Greiner
1Department of Pathology, University of Connecticut Health Center, Farmington 06030.
Abstract:
Mice homozygous for the viable motheaten (me(v)) allele manifest abnormalities in thymocytopoiesis, are severely immunodeficient, and develop autoimmune disorders early in life. Premature thymic involution occurs in me(v)/me(v) mice, and their bone marrow prothymocytes are unable to repopulate the thymus of adoptive recipients following intravenous (i.v.) transfer. However, analysis of thymocytopoiesis following intrathymic (i.t.) adoptive transfer of bone marrow from me(v)/me(v) mice demonstrates the presence of normal numbers of prothymocytes. To investigate intrathymic development in me(v)/me(v) mice, we determined intrathymic precursor cell number and activity. Dual labeling analyses showed that an involuted me(v)/me(v) thymus is relatively enriched (fivefold) in CD4-CD8- thymocytes (intrathymic precursor phenotype) compared with wild-type (+/+) thymus. However, thymocytes from me(v)/me(v) mice were deficient in precursor activity when adoptively transferred i.t. into irradiated recipients. Thymocytes recovered from the involuted thymus of aged or steroid-treated normal mice also displayed reduced precursor activity. However, the phenotypic profile of thymocyte subsets from steroid-treated mice was enriched in single positive cells (mature phenotype) and was distinctly different from the subset distribution of thymocytes in me(v)/me(v) and aged mice. These results suggest that intrathymic precursor activity in me(v)/me(v) mice is decreased, and may be reflective of decreased prothymocyte seeding to the thymus in vivo. In addition, the results suggest that the thymic involution in me(v)/me(v) mice is not due solely to effects of corticosteroids.
Insights
Mice with the viable motheaten (me(v)) mutation show reduced intrathymic T-cell precursor activity, contributing to thymic involution and immunodeficiency. This suggests impaired thymus seeding, not just corticosteroid effects.
Area of Science:
- Immunology
- Developmental Biology
- Genetics
Background:
- Mice homozygous for the viable motheaten (me(v)) allele exhibit thymocytopoiesis abnormalities, severe immunodeficiency, and early-onset autoimmune disorders.
- These mice experience premature thymic involution, with bone marrow prothymocytes unable to repopulate the thymus after intravenous transfer.
Purpose of the Study:
- To investigate intrathymic T-cell development and precursor cell activity in me(v)/me(v) mice.
- To determine if thymic involution in me(v)/me(v) mice is solely due to corticosteroid effects.
Main Methods:
- Adoptive transfer of bone marrow and thymocytes (intravenous and intrathymic) into irradiated recipients.
- Dual labeling analyses to assess thymocyte subset distribution and precursor cell numbers.
- Phenotypic analysis of thymocyte subsets in me(v)/me(v), aged, and steroid-treated mice.
Main Results:
- me(v)/me(v) thymuses are enriched in CD4-CD8- thymocytes (intrathymic precursor phenotype) but show deficient precursor activity upon intrathymic transfer.
- Thymocytes from aged or steroid-treated mice also exhibit reduced precursor activity, but with distinct phenotypic profiles.
- The thymic involution in me(v)/me(v) mice is not solely attributable to corticosteroid action.
Conclusions:
- Intrathymic T-cell precursor activity is decreased in me(v)/me(v) mice, potentially due to reduced prothymocyte seeding.
- Thymic involution in these mice is a complex process not solely driven by corticosteroids.