Polyclonal CD4(+) T cell tolerance is established by distinct mechanisms, according to self-peptide expression patterns

Studies of mouse monoclonal CD4(+) T cell repertoires have revealed several mechanisms of self-tolerance, however, which mechanisms operate in normal repertoires is unclear. Here, polyclonal CD4(+) T cells specific for green fluorescent protein expressed in different organs were studied, allowing determination of the effects of specific expression patterns on the same epitope-specific T cells. Peptides presented uniformly by thymic antigen-presenting cells were tolerated by clonal deletion, whereas thymus-excluded peptides were ignored. Peptides with limited thymic expression induced partial clonal deletion and impaired effector but enhanced regulatory T cell potential. These mechanisms were also active for T cell populations specific for endogenously expressed self-antigens. Thus, immune tolerance of polyclonal CD4(+) T cells is maintained by distinct mechanisms, according to self-peptide expression patterns.