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 HLA class I alleles A2, B7, or B27 in their fully native form (HLAnat) or as hybrid molecules (HLAhyb) of the HLA alpha1/alpha2 domains linked to the H-2Kb 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 HLAhyb molecules induced stronger xeno-CD8+ T cell responses in vitro, additional effector mechanisms must be active in vivo because HLAnat skin grafts were rejected faster by non-TgM; 2) gene knockout recipients showed that xenorejection of HLAnat and, unexpectedly, HLAhyb grafts doesn't depend on CD8+ or CD4+ T cells or B cells; 3) each HLAhyb 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-HLAhyb 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.
Borenstein
S H
SH
Institute of Medical Science, University of Toronto, The Hospital for Sick Children, Toronto, Canada.
Graham
J
J
Zhang
X L
XL
Chamberlain
J W
JW
D000483:Alleles; D000818:Animals; D015478:Antigens, Heterophile / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D005786:Gene Expression Regulation / Q000276:immunology; D005819:Genetic Markers / Q000276:immunology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006183:H-2 Antigens / Q000096:biosynthesis / Q000235:genetics; D006680:HLA Antigens / Q000096:biosynthesis / Q000235:genetics*; D015789:HLA-A2 Antigen / Q000096:biosynthesis / Q000235:genetics; D015796:HLA-B27 Antigen / Q000096:biosynthesis / Q000235:genetics; D015793:HLA-B7 Antigen / Q000096:biosynthesis / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics*; D006650:Histocompatibility Testing; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016038:Skin Transplantation / Q000276:immunology; D019076:Transgenes / Q000276:immunology; D014407:Tumor Cells, Cultured
D015478:Antigens, Heterophile; D005819:Genetic Markers; D006183:H-2 Antigens; D006680:HLA Antigens; D015789:HLA-A2 Antigen; D015796:HLA-B27 Antigen; D015793:HLA-B7 Antigen; D015395:Histocompatibility Antigens Class I