Age-Associated Thymic Atrophy in the Mouse Is Due to a Deficiency Affecting Rearrangement of the TCR during Intrathymic T Cell Development

Involution of the thymus is a feature of age and precedes inefficient functioning of the immune system. C57BL/10 mice show an 83% reduction in number of thymocytes between 3 and 20 mo of age, with a significant decline in each of the thymic subsets defined by their expression of CD4 and CD8. The similar percentage contribution of each subset to the whole at 3, 12, and 20 mo suggests a lesion in the T cell developmental pathway within an early subset. The CD3^-CD4^-CD8^- subset showed a significant decline in number by 20 mo of age, but despite this reduction, no significant difference was noted in the number of CD44⁺CD25^- cells, the earliest stage of this subset between 3 and 20 mo of age. A significant decline in the number of their progeny, the CD44⁺CD25⁺, and the progeny of these cells, the CD44^-CD25⁺ cells, was noted by 12 mo of age. Expression of CD25 within this subset is associated with rearrangement of TCR β-chain genes. F₅ transgenic mice, carrying a complete TCR-αβ transgene under the control of a CD2 minigene cassette on a C57BL/10 background, showed no age-associated thymic atrophy in any of the defined thymic subsets over the same period as the normal C57BL/10 mice. Similar results were noted with mice carrying the same transgene but which in addition were also RAG-1^-. The results indicate that age-associated thymic involution was associated with problems with rearrangement of the TCR β-chain genes affecting the production of thymocytes.