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

Research output: Contribution to journalArticleResearchpeer-review

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., ... 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
Van Braeckel-Budimir, Natalija ; Gras, Stephanie ; Ladell, Kristin ; Josephs, Tracy M. ; Pewe, Lecia ; Urban, Stina L. ; Miners, Kelly L. ; Farenc, Carine ; Price, David A. ; Rossjohn, Jamie ; Harty, John T. / A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene. In: Immunity. 2017 ; Vol. 47, No. 5. pp. 835-847.
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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.",
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Van Braeckel-Budimir, N, Gras, S, Ladell, K, Josephs, TM, Pewe, L, Urban, SL, Miners, KL, Farenc, C, Price, DA, Rossjohn, J & Harty, JT 2017, 'A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene', Immunity, vol. 47, no. 5, pp. 835-847. https://doi.org/10.1016/j.immuni.2017.10.013

A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene. / Van Braeckel-Budimir, Natalija; Gras, Stephanie; Ladell, Kristin; Josephs, Tracy M.; Pewe, Lecia; Urban, Stina L.; Miners, Kelly L.; Farenc, Carine; Price, David A.; Rossjohn, Jamie; Harty, John T.

In: Immunity, Vol. 47, No. 5, 21.11.2017, p. 835-847.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene

AU - Van Braeckel-Budimir, Natalija

AU - Gras, Stephanie

AU - Ladell, Kristin

AU - Josephs, Tracy M.

AU - Pewe, Lecia

AU - Urban, Stina L.

AU - Miners, Kelly L.

AU - Farenc, Carine

AU - Price, David A.

AU - Rossjohn, Jamie

AU - Harty, John T.

PY - 2017/11/21

Y1 - 2017/11/21

N2 - 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.

AB - 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.

KW - experimental cerebral malaria

KW - immune response genes

KW - malaria

KW - naive CD8 T cells

KW - TCR bias

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