CD8+ T cells are necessary for recognition of allelic, but not locus-mismatched or xeno-, HLA class I transplantation antigens

Although HLA transgenic mice (HLA TgM) could provide a powerful approach to investigate human MHC-specific T cell responsiveness, the extent to which these molecules are recognized by the mouse immune system remains unclear. We established TgM expressing III,A class I alleles A2, B7, or B27 in their fully native form (HLA(nat)) or as hybrid molecules (HLA(hyb)) Of the HLA alpha1/alpha2 domains linked to the H-2K(b) alpha3, transmembrane, and cytoplasmic domains (i.e., to maintain possible species-specific interactions). Comparison of each as xeno- (i.e., by non TgM) vs allo- (i.e., by TgM carrying an alternate HLA allele) transplantation Ags revealed the following: 1) Although HLA(hyb) molecules induced stronger xeno-CD8(+) T cell responses in vitro, additional effector mechanisms must be active in vivo because HLA(nat) skin grafts were rejected faster by non-TgM; 2) gene knockout recipients showed that xenorejection of HLA(nat) and, unexpectedly, HLAhyb grafts doesn't depend on CD8+ or CD4+ T cells or B cells; 3) each HLA(hyb) strain developed tolerance to "self" but rejected allele- (-B27 vs -B7) and locus- (-B vs -A) mismatched grafts, the former requiring CD8(+) T cells, the latter by CD8(+) T cell-independent mechanisms. The finding that recognition of xeno-HLA(hyb) does not require CD8(+) T cells while recognition of the identical molecule in a strictly allo context does, demonstrates an alpha1/alpha2 domain-dependent difference in effector mechanism(s), Furthermore, the CD8(+) T cell-independence of locus-mismatched rejection suggests the degree of similarity between self and non-self alpha1/alpha2 determines the effector mechanism(s) activated. The HLA Tg model provides a unique approach to characterize these mechanisms and develop tolerance protocols in the context of human transplantation Ags.