Natalija Van Braeckel-Budimir, Stephanie Gras, Kristin Ladell, Tracy M. Josephs, Lecia Pewe, Stina L. Urban, Kelly L. Miners, Carine Farenc, David A. Price, Jamie Rossjohn, John T. Harty

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 GAP5040-48 epitope in mice expressing the MHC class I allele H-2D(b). GAP5040-48-specific CD8(+) T cell responses emerged from a very large pool of naive Vβ8.1(+) precursors, which dictated susceptibility to cerebral malaria and conferred protection against recombinant Listeria monocytogenes infection. Structural analysis of a prototypical Vβ8.1(+) TCR-H-2D(b)-GAP5040-48 ternary complex revealed that germline-encoded complementarity-determining region 1β residues present exclusively in the Vβ8.1 segment mediated essential interactions with the GAP5040-48 peptide. Collectively, these findings demonstrated that Vβ8.1 functioned as an Ir gene that was indispensable for immune reactivity against the malaria GAP5040-48 epitope.