DOSE-DEPENDENT T-CELL TOLERANCE TO AN IMMUNODOMINANT SELF-PEPTIDE

We have previously described a model of tolerance to self peptides in a mouse transgenic (Tg) line producing secreted hen egg-white lysozyme (HEL). The HEL cDNA was placed under the control of a ubiquitous prom oter expressed early in embryogenesis, so that HEL should be present i n Tg mice throughout the development of the immune system. Since indiv idual HEL Tg mice express different amounts of serum HEL, we were prev iously able to show that H-2(d) mice with HEL blood level > 10 ng/ml a re tolerant to HEL and to the immunodominant (LD) peptide 108-116. How ever, autoreactive T lymphocytes recognizing the HEL subdominant (SD) peptides 74-96 and 1-18 still persist and the SD-specific responses di sappear at higher blood HEL concentrations. In the present work, we ha ve studied HEL Tg H-2(d) mice with HEL serum levels < 10 ng/ml (HEL-lo w Tg animals). We find that 50 % of Tg animals with HEL blood concentr ation < 2 ng/ml are responsive to HEL in T cell proliferation assays, although these responses are lower than those seen in non-Tg control m ice. The HEL-specific T lymphocytes react only with 15-mer overlapping peptides encompassing the single H-2(d) ID region of HEL (residues 10 2-122); whereas the 9-mer minimal ID peptide 108-116, which strongly t riggers non-Tg T cells, is unable to stimulate auto-reactive T cells i n vitro from HEL-low Tg mice. Altogether, our results suggest that T l ymphocytes specific for the minimal ID peptide are deleted or inactiva ted, while T cell clones of lower affinity and reacting with epitopes on longer peptides persist. Thus, the high affinity ID peptide-specifi c T cell clones can be negatively selected even in the presence of low amounts of HEL.