Mechanisms, manifestations, and failures of self-tolerance.

We have developed transgenic (Tg) mice that express the influenza virus A/PR/8/34 hemagglutinin (PR8 HA) as a well-characterized model antigen with which to analyze factors governing tolerance and autoreactivity among CD4+ T and B cells. To analyze how the expression of self-antigens in varying amounts and in different cell types and tissues affects these processes, we have used a variety of promoters and enhancers to drive HA expression. By mating these HA Tg mice with Tg mice-expressing HA-specific major histocompatibility complex (MHC) class II-restricted T cell receptors (TCRs), we have shown that variations in the expression of the HA in different HA Tg lineages can cause CD4+ T cells with identical specificity for a self-peptide either to be deleted (to varying degrees) or to undergo selection to become CD4+ CD25+ regulatory T cells. In addition, a high intrinsic affinity of the TCR for a self-peptide appears to be required for thymocytes to undergo selection to become CD4+ CD25+ regulatory T cells. We have also shown that separate populations of HA-specific B cells that participate at distinct phases of the immune response to the HA in BALB/c mice differ significantly in their sensitivity to negative selection by the neo-self HA. Together, these studies demonstrate that both the diversity of the CD4+ T cell and B cell responses to the HA and variations in the expression of the HA in HA Tg mice can significantly affect the mechanisms and extent of CD4+ T and B cell tolerance induction.