AGE-ASSOCIATED THYMIC ATROPHY IN THE MOUSE 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 development al pathway within an early subset. The CD3(-)CD4(-)CD8(-) subset showe d a significant decline in number by 20 mo of age, but despite this re duction, no significant difference was noted in the number of CD44(+)C D25(-) 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, wa s noted by 12 mo of age. Expression of CD25 within this subset is asso ciated with rearrangement of TCR beta-chain genes. F-5 transgenic mice , carrying a complete TCR-alpha beta transgene under the control of a CD2 minigene cassette on a C57BL/10 background, showed no age-associat ed thymic atrophy in any of the defined thymic subsets over the same p eriod as the normal C57BL/10 mice. Similar results were noted with mic e carrying the same transgene but which in addition were also RAG-1(-) . The results indicate that age-associated thymic involution was assoc iated with problems with rearrangement of the TCR beta-chain genes aff ecting the production of thymocytes.