Expression of major histocompatibility complex class I antigens at low levels in the thymus induces T cell tolerance via a non‐deletional mechanism

Transgenic CBA (H‐2^k haplotype) mice expressing the H‐2 K^b major histocompatibility complex (MHC) class I gene under control of transcriptional promoter elements from a milk protein gene display high‐level H‐2 K^b transcription in lactating mammary glands and low‐level transcription in skin and thymus of male and virgin female transgenic mice. However, H‐2 K^b antigen could be detected only in lactating mammary gland epithelial cells by immunohistological methods. All transgenic mice are tolerant of H‐2 K^b since they fail to reject skin grafts from mice expressing H‐2 K^b molecules. Furthermore, anti‐H‐2 K^b cytotoxic responses could not be generated using responder T cells from transgenic mice but T cells from the same mice proliferated, in the presence of interleukin‐2, in response to stimulator cells expressing H‐2 K^b. Tolerance to H‐2 K^b is induced in the thymus since CBA mice grafted with thymus tissue from transgenic mice fail to reject H‐2 K^b disparate skin grafts. However, experiments with double‐transgenic mice also expressing a T cell receptor with anti‐H‐2 K^b specificity reveal that tolerance induction is not brought about by elimination of thymocytes bearing H‐2 K^b‐reactive receptors. Instead, a non‐deletional mechanism which results in down‐modulation of both CD8 and T cell receptor expression in peripheral T cells correlates with the induction of tolerance in these mice. These data reveal that extremely low levels of self‐antigen expression in the thymus are sufficient to induce tolerance via non‐deletional mechanisms.