EXPRESSION OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I ANTIGENS AT LOW-LEVELS IN THE THYMUS INDUCES T-CELL TOLERANCE VIA A NONDELETIONAL MECHANISM

Transgenic CBA (H-2k 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 Tcell 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.