Thymic Involution in Viable Motheaten (meυ) Mice is Associated with a Loss of Intrathymic Precursor Activity

Mice homozygous for the viable motheaten (meυ) allele manifest abnormalities in thymocytopoiesis, are severely immunodeficient, and develop autoimmune disorders early in life. Premature thymic involution occurs in meυ/meυ 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 meυ/meυ mice demonstrates the presence of normal numbers of prothymocytes. To investigate intrathymic development in meυ/meυ mice, we determined intrathymic precursor cell number and activity. Dual labeling analyses showed that an involuted meυ/meυ thymus is relatively enriched (fivefold) in CD4– CD8– thymocytes (intrathymic precursor phenotype) compared with wild-type (+/+) thymus. However, thymocytes from meυ/meυ 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 meυ/meυ and aged mice. These results suggest that intrathymic precursor activity in meυ/meυ 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 meυ/meυ mice is not due solely to effects of corticosteroids.