A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene

Immune response (Ir) genes, originally proposed by Baruj Benacerraf to explain differential antigen-specific responses in animal models, have become synonymous with the major histocompatibility complex (MHC). We discovered a non-MHC-linked Ir gene in a T cell receptor (TCR) locus that was required for CD8(+) T cell responses to the Plasmodium berghei GAP50(40-48) epitope in mice expressing the MHC class I allele H-2D(b). GAP50(40-48)-specific CD8(+) T cell responses emerged from a very large pool of naive V beta 8.1(+) precursors, which dictated susceptibility to cerebral malaria and conferred protection against recombinant Listeria monocytogenes infection. Structural analysis of a prototypical V beta 8.1(+) TCR-H-2D(b)-GAP50(40-48) ternary complex revealed that germline- encoded complementarity-determining region 1 beta residues present exclusively in the V beta 8.1 segment mediated essential interactions with the GAP50(40-48) peptide. Collectively, these findings demonstrated that V beta 8.1 functioned as an Ir gene that was indispensable for immune reactivity against the malaria GAP50(40-48) epitope.