Genetic analysis of age-related thymic involution

Thymic involution is a gradual decline in thymus function and integrity during aging. The involution of the thymus and the age-related changes in T-cell development in the thymus have been postulated to be associated with the higher susceptibility of the elderly to some infections, autoimmune diseases, and cancers. A better understanding of the mechanisms that govern age-related thymic involution and immune dysfunction will lead to a better understanding of how to maintain normal T-cell function in the elderly and will help reduce their susceptibility to infectious disease and cancer. The overall objectives of the studies presented in this dissertation were to determine whether genetic factors influence age-related thymic involution and to determine the role of IL-12 in T-cell development during age-related thymic involution. In the first part of the study, thymic involution was characterized in two strains of mice, the DBA/2 (D2) strain and the C57BL/6 (B6) strain, which exhibit early-age onset and late-age onset thymic involution, respectively. The results of this comprehensive analysis suggest that genetic differences between the B6 and D2 strains of mice affect the pace of thymic involution profoundly. The second part of the study focused on analysis of the function of interleukin (IL)-12 in T-cell development and age-related thymic involution. IL-12 was found to exhibit synergy with IL-2, IL-7, and anti-CD3 in thymocyte stimulation. Analysis of IL-12b-knockout mice of different ages revealed that these mice exhibited accelerated thymic involution in old age. Based on these data, several possible mechanisms that might be involved in the synergistic effects of IL-12, IL-7, and IL-2 have been hypothesized: (i) IL-12 may interact directly with other signaling molecules, such as the common gamma chain, and function as a co-stimulator; (ii) downstream molecules in the IL-12 signaling pathway may stimulate the production of IL-2 and IL-7 at the level of transcription; (iii) IL-12 may function to maintain thymopoiesis in aged mice via its direct effect on maintaining the epithelial cells to secrete IL-7 in the thymus; and (iv) loss of IL-12 with age may be an important contributing factor in age-related thymic involution.