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-2k haplotype) mice expressing the H-2 Kb major histocompatibility complex (MHC) class I gene under control of transcriptional promoter elements from a milk protein gene display high-level H-2 Kb transcription in lactating mammary glands and low-level transcription in skin and thymus of male and virgin female transgenic mice. However, H-2 Kb antigen could be detected only in lactating mammary gland epithelial cells by immunohistological methods. All transgenic mice are tolerant of H-2 Kb since they fail to reject skin grafts from mice expressing H-2 Kb molecules. Furthermore, anti-H-2 Kb 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 Kb. Tolerance to H-2 Kb is induced in the thymus since CBA mice grafted with thymus tissue from transgenic mice fail to reject H-2 Kb disparate skin grafts. However, experiments with double-transgenic mice also expressing a T cell receptor with anti-H-2 Kb specificity reveal that tolerance induction is not brought about by elimination of thymocytes bearing H-2 Kb-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.
Husbands
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SD
Division of Molecular Immunology, National Institute for Medical Research, Mill Hill, London, GB.
Schönrich
G
G
Arnold
B
B
Chandler
P R
PR
Simpson
E
E
Philpott
K L
KL
Tomlinson
P
P
O'Reilly
L
L
Cooke
A
A
Mellor
A L
AL
D000818:Animals; D005260:Female; D015870:Gene Expression; D006183:H-2 Antigens / Q000032:analysis* / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000502:physiology*
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse