The thymus is the organ of T cell development and is responsible for depleting self-reactive T clones via negative selection. However, natural aging involves the progressive loss of FoxN1, which leads to age-related thymic atrophy. Aging also causes an increased incidence of autoimmune disorders, in which Th17 cells are known to be involved. Because Th17 cells are confirmed to be generated in the thymus, it can be questioned whether atrophied thymus-generated auto-reactive Th17 cells cannot be completely depleted and therefore contribute to the greater risk of autoimmunity in the elderly. Using a mouse model (FoxN1 conditional knockout, FC) that mimics an aged thymus, we investigated this question. We found the proportion of natural Th17 (nTh17) cells, which are found in the thymus, tended to be higher after induction in an atrophied thymus compared to a normal thymus. However, peripheral Th17 cells generated from the atrophied thymus remained unchanged. Despite no change in peripheral Th17 proportions, when transferred into a young healthy host (RAG knockout mouse) lacking T and B cells, these peripheral Th17 cells caused inflammation and cellular infiltration in the colon and lung but not in the salivary or lacrimal gland. In addition, we induced experimental autoimmune encephalomyelitis (EAE), and we found no difference in disease onset or severity between mice with an atrophied thymus and those with a normal thymus. These data imply that self-reactive Th17 cells generated from an aged atrophied thymus do escape depletion and are released into the periphery. These cells have characteristics of tissue-specific self-reactivity, which may be related to the local microenvironment, such as existence of bacteria. In conclusion, thymic atrophy results in a defective process of negative selection and therefore allows auto-reactive Th17 cells to survive and leave the thymus. In the periphery, the auto-reactive Th17 cells can cause tissue-specific age-associated development of autoimmune phenotype. Our data can contribute to a mechanistic understanding of age-associated autoimmune disease and therefore is likely to contribute meaningfully to evidence-based therapeutically useful approaches to target self-reactive Th17 cells in age-associated autoimmune disease.
|Commitee:||Berg, Rance, Mummert, Mark|
|School:||University of North Texas Health Science Center at Fort Worth|
|Department:||Microbiology and Immunology|
|School Location:||United States -- Texas|
|Source:||MAI 52/02M(E), Masters Abstracts International|
|Keywords:||Aging, Autoimmunity, Colon, Elderly, Thymus|
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