A role for Fas in negative selection of thymocytes in vivo

To seek information on the role of Fas in negative selection, we examined subsets of thymocytes from normal neonatal mice versus Fas-deficient lpr/lpr mice injected with graded doses of antigen. In normal mice, injection of 1-100 mu g of staphylococcal enterotoxin B (SEB) induced clonal elimination of SEB-reactive V beta 8(+) cells at the level of the semi-mature population of HSA(hi) CD4(+)8(-) cells found in the thymic medulla; deletion of CD4(+)8(+) cells was minimal. SEE injection also caused marked elimination of V beta 8(+) HSA(hi) CD4(+)8(-) thymocytes in lpr/lpr mice. Paradoxically, however, elimination of these cells in lpr/lpr mice was induced by low-to-moderate doses of SEB (less than or equal to 1 mu g) but not by high doses (100 mu g). Similar findings applied when T cell receptor transgenic mice were injected with specific peptide. These findings suggest that clonal elimination of semi-mature medullary T cells is Fas independent at low doses of antigen but Fas dependent at high doses. Previous reports documenting that negative selection is not obviously impaired in lpr/lpr mice could thus reflect that the antigens studied were expressed at only a low level.