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

S. H. Borenstein, J. Graham, X. L. Zhang, J. W. Chamberlain

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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 (HLA(nat)) or as hybrid molecules (HLA(hyb)) of the HLA αl/α2 domains linked to the H-2Kb α3, 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, HLA(hyb) 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 αl/α2 domain-dependent difference in effector mechanism(s). Furthermore, the CD8+ T cell-independence of locus-mis-matched rejection suggests the degree of similarity between self and non-self αl/α2 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.

Original languageEnglish (US)
Pages (from-to)2341-2353
Number of pages13
JournalJournal of Immunology
Volume165
Issue number5
DOIs
StatePublished - Sep 1 2000
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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