Altered Thymic and Peripheral T-Lymphocyte Repertoire Preceding Onset of Diabetes in NOD Mice

Abstract

Insulitis occurs by 5 wk of age in all NOD mice. However, diabetes is detectable only after 3-5 mo of age and only in approximately 50% of females and 10% of males in our colony. Therefore, it is predictable that changes in the T-lymphocyte repertoire of diabetes-prone mice occur and predispose them to disease. We demonstrate here that an altered (with respect to control BALB/cJ mice) thymic T-lymphocyte maturation reflected by a depletion (approximately 12%) of CD4+CD8+ T lymphocytes and a reciprocal increase in CD4-CD8- T lymphocytes precedes the onset of diabetes. This depletion was detected only approximately 3 mo after insulitis and is manifested by a specific loss (approximately 3%) of immature T lymphocytes bearing V beta 8lo (lo is a relative level of expression) T-lymphocyte receptor. By onset of diabetes, an even greater decrease (approximately 35%) of CD4+CD8+ and a reciprocal increase of CD4-CD8- T lymphocytes were apparent and accompanied by the same depletion (3%) of V beta 8 lo T lymphocytes. Administration of cyclophosphamide (CY), which accelerates the appearance of diabetes in NOD mice, caused similar depletions of CD4+CD8+ and V beta 8lo thymic T lymphocytes. The same alterations in the distribution of these thymic T-lymphocyte subsets were evident even earlier in insulitis- and diabetes-free NON mice, indicating that these changes in thymic T-lymphocyte development may be necessary but not sufficient to give rise to diabetes. Despite the common genetic origin of NOD and NON mice, differences at their MHC-linked and -unlinked loci may account for their differential susceptibility to diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)