ABNORMALITIES IN THE EXPORT AND FATE OF RECENT THYMIC EMIGRANTS IN DIABETES-PRONE BB W RATS/

Abnormalities in postthymic T cell development in the BB/W rat model o f autoimmune insulin-dependent diabetes mellitus (IDDM) result in part from a lymphopenia (lyp) gene defect. To better characterize these ab normalities, the phenotypes of T cells from diabetes-prone (DP) and di abetes-resistant (DR) coisogenic rats were analyzed by multiparameter flow immunocytometry (FCM). Marked decreases in the numbers of Thy1(-) RT6(+) T cells, most of which are CD8(+), were documented in DP rats by live-gating. Conversely, an approximately 3-fold increase was obser ved in the percentage of Thy1(+) RT6(-) T cells, which normally serve as the precursors of both Thy1(-) RT6(+) and Thy1(-) RT6(-) T cell sub sets in rats. These results suggested that, at a minimum, an arrest in maturation of the Thy1(+) precursors of RT6(+) T cells occurs postthy mically in DP rats. To determine more precisely the stage(s) in T cell development at which lymphopenia occurs, the export and fate of recen t thymic emigrants (RTE's) and their immediate descendants in DP rats was traced after intrathymic (i.t.) labelling with fluorescein isothio cyanate (FITC). The results showed that in DP, as compared with DR, ra ts: 1) 5-fold fewer RTE's are exported from the thymus per 24 hr; 2) m ore than 80% of the RTE's are CD4(+); 3) most of the immediate descend ants of RTE's disappear from the peripheral lymphoid tissues within on e week after export from the thymus; and 4) few of the descendants of the RTE's that do survive differentiate into RT6(+) T cells. Staining with propidium iodide revealed that a significantly higher proportion of Thy1(+) T cells in DP than in DR rats are in cycle (S/G2/M), thereb y accounting for their disproportionately high numbers relative to RTE 's. These results indicate that, in addition to defective thymic expor t, most of the immediate descendants of RTE's in DP rats undergo non-p roductive proliferation and death at the time (3-7 days postthymic) at which their counterparts in DR rats differentiate into Thy1(-) RT6(+) T cells. The resulting deficiency of immunoregulatory T cells, acting in concert with defective intrathymic selection of effector T cell pr ecursors, appears to conspire to markedly enhance the predisposition o f DP rats to autoimmunity.