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

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

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13 Citations (Scopus)

Abstract

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-2Db. 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-2Db-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. CD8+ T cells that recognize MHC I-peptide complexes contribute to protection or pathogenesis after infection. Van Braeckel-Budimir et al. demonstrate that a germline-encoded component of the T cell receptor functions as an Immune response (Ir) gene, controlling the CD8+ T cell response against a malaria epitope and the outcome of infection.

Original languageEnglish
Pages (from-to)835-847
Number of pages14
JournalImmunity
Volume47
Issue number5
DOIs
Publication statusPublished - 21 Nov 2017

Keywords

  • experimental cerebral malaria
  • immune response genes
  • malaria
  • naive CD8 T cells
  • TCR bias

Cite this

Van Braeckel-Budimir, N., Gras, S., Ladell, K., Josephs, T. M., Pewe, L., Urban, S. L., Miners, K. L., Farenc, C., Price, D. A., Rossjohn, J., & Harty, J. T. (2017). A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene. Immunity, 47(5), 835-847. https://doi.org/10.1016/j.immuni.2017.10.013