Reduced diversity of CTLs specific for multiple minor histocompatibility antigens relative to allograft rejection in vivo.

Minor histocompatibility (H) antigens stimulate in vivo rejection of allografts compatible for the MHC and are recognized by CTLs in short term in vitro assays. CTLs generated by the in vivo priming and in vitro boosting of mice with spleen cells incompatible for multiple minor H Ags are specific for a limited number of dominant Ags (peptides). We have addressed the issue of the identity of the Ags that stimulate rejection of solid tissue allografts vs the H Ags recognized by CTLs. C57BL/6 recipients reject skin grafts from BALB.B and CXB recombinant inbred strains with no significant differences in survival times. Primary grafts from these same strains prime for accelerated rejection of second-set grafts from all CXB strains regardless of inheritance of dominant Ags detected by CTLs. However, CTLs primed by these allografts and boosted in vitro do not exhibit ranges of reactivity with lymphoblast targets from CXB strains predicted by in vivo rejection, suggesting that CTLs primed by multiple Ag-incompatible skin grafts do not recognize all H Ags that stimulate allograft rejection. The fact that first- and second-set BALB.B skin grafts prime for accelerated rejection of 11/13 congenic strains defining single BALB/c minor H Ags indicates that multiple H Ags stimulate allograft rejection. However, CTLs from C57BL/6 mice primed with BALB.B grafts and boosted with BALB.B spleen cells recognize only the H4 Ag from this panel of congenic strains. Limited diversity of the CTL response is corroborated by the recognition of three minor H peptides (including H4 as the most prominent) eluted from Kb molecules from a BALB.B tumor by these CTLs. These results indicate that CTLs recognize only a limited number of Ags operative in vivo and do not accurately reveal the complexity of the antigenic specificity of the in vivo response.