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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 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-GAP50_40-48 ternary complex revealed that germline-encoded complementarity-determining region 1β residues present exclusively in the Vβ8.1 segment mediated essential interactions with the …