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

Abstract

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.

CD4 T Cell Tolerance to Human C-reactive Protein, an Inducible Serum Protein, Is Mediated by Medullary Thymic Epithelium

“…Several neo–self-antigens under direction of putatively tissue-specific promoters have been found to be expressed in the thymus of transgenic mice. These include the promoters of rat insulin II (41, 42), rat elastase I (43), guinea pig α-lactalbumin, human beta globin (44, 45), keratin-IV (46), and metallothionein (47). Thymic expression of different model antigens driven by these heterologous regulatory elements was often variable and usually found in some but not all transgenic lines, consistent with the notion that the integration site and/or the copy number influence expression.…”

Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance

“…The thymus has the capacity to express a wide range of TSA and in that way it synergizes with the peripheral tolerance machinery to ensure that the mature T cell pool of every individual is tolerant to self. This extraordinary feature of the thymus has initially been recognized as an artifact of transgenics, as it has been documented that tissue specific transgenic constructs are ectopically expressed in the thymus [43][44][45] .…”

Competition Between MHC Class I Alleles for Cell Surface Expression Alters CTL Responses to Influenza A Virus

“…Therefore, we looked for a different in vivo model where competition between MHC class I alleles may have resulted in greater down-regulation of the expression of one or two alleles. H-2K b -transgenic CBA mice (CBK) (33,34) were good candidates as these mice expressed the three MHC class I molecules implicated in the strongest competition that we had found: H-2K surface level of H-2K b molecules as compared with cells from B6 mice, but this high level of expression was not accompanied by a general increase in total MHC class I, as staining of splenic cells with the pan class I Ab M1/42 was similar for CBK and CBA mice (data not shown). Therefore, the levels of cell surface expression of H-2K k and H-2D k molecules on splenic T lymphocytes, B lymphocytes, and DCs were compared between CBA and CBK mice (Fig.…”