A single T-cell in the thymus must face a gauntlet of self-antigens. This process represents a very delicate balance, because if the criteria for negative selection is too stringent, then the majority of the repertoire would be eliminated. If the criteria is too low, then autoreactive T-cell would be prevalent. To explore in a critical manner this critical aspect of T-cell biology, the investigator has developed a comprehensive system composed of a transgenic mouse expressing a TCR specific for an allelic determinant of murine hemoglobin, Hb(64-76), and a series of seven variant ligands representing a continuum of different affinities. The effect on the type and extent of tolerance of the in vivo expression of: 1) endogenous HB(64-76); 2) high levels of HB(64-76) as a transgene; 3) variants of HB (64-76) as a transgene will be ascertained. Also, the effect of changing the set point of tolerance in the thymus using inducible expression of CD4 will be explored. The concept of molecular mimicry will be defined by determining the relationship between an infectious process and autoimmunity using Hb and its variants expressed in Salmonella. They may also provide insight into how to control autoreactive T-cells, including preventing their activation to ameliorate autoimmune response.
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