Determinant selection for T-cell tolerance in HEL-transgenic mice: Dissociation between immunogenicity and tolerogenicity

The induction of T-cell tolerance to self-antigens has been extensively characterized for immunodominant (ID) regions. However, tolerance toward other minor self-determinants has received less attention. In the H-2(d) haplotype, HEL contains a single ID determinant (region 102-120) presented by I-E(d) MHC class II molecules. The present study evaluates the role of subdominant and cryptic HEL regions in maintaining tolerance. We have generated a mutated HEL antigen, HELμ, whose ID region does not bind to I-E(d). Lymph node cells from HEL-immunized mice proliferated strongly to HELμ in vitro. Two new stimulatory regions common to HEL and HELμ were uncovered. They are produced during antigen processing and prime specific T lymphocytes. HEL-Tg mice were tolerant to these determinants, thus confirming their in vivo presentation. These HEL regions were as tolerogenic as the HEL ID determinant, despite their poor immunogenicity. These results demonstrate that there is not always a correlation between tolerogenicity and immunogenicity, a finding that may be critical for understanding T-cell tolerance.