MATURE MAINSTREAM TCR-ALPHA-BETA(-SELECTIN MEDIATE ACTIVE TOLERANCE IN THE NONOBESE DIABETIC MOUSE()CD4(+) THYMOCYTES EXPRESSING L)

Pathogenic autoreactive T lymphocytes are mediators of spontaneous ins ulin-dependent diabetes in nonobese diabetic (NOD) mice. This is demon strated by their capacity to transfer diabetes into syngeneic immunoin competent recipients. In addition, especially in prediabetic NOD mice, peripheral CD4(+) T lymphocytes were identified that are highly effec tive, in conventional mixing cotransfer experiments, at preventing dis ease transfer. The present data demonstrate that mature heat-stable Ag -TCR alpha beta(+)CD8- thymocytes from prediabetic NOD mice also expre ss this inhibitory capacity, Selection using an L-selectin (CD62L)-spe cific Ab showed that TCR alpha beta(+)CD4(+)CD62L(+) thymocytes, emerg ing from the mainstream differentiation pathway, concentrate this abil ity to regulate autoreactive effecters. Compared with mature TCR alpha beta(+)CD8(-) thymocytes, significantly lower numbers of TCR alpha be ta(+)CD4(+)CD62L(+) were sufficient to achieve an efficient inhibition of disease transfer into NOD-scid recipients, This protective ability was potentiated following in vitro culture in the presence of IL-7, I n contrast, TCR alpha beta(+)CD62L(-) thymocytes, highly enriched in c lass I-restricted NK T cells, were unable to influence diabetes transf er. Identical results were obtained using thymocytes that have been cu ltured in vitro for 4 days in the presence of IL-7, These results supp ort the active role in NOD mice of a thymus-derived CD4(+) subset that controls peripheral pathogenic autoimmune effecters.