Fixing an irrelevant TCR alpha chain reveals the importance of TCR beta diversity for optimal TCR alpha beta pairing and function of virus-specific CD8+ T cells

Eur J Immunol. 2010 Sep;40(9):2470-81. doi: 10.1002/eji.201040473.

Abstract

TCR repertoire diversity can influence the efficacy of CD8(+) T-cell populations, with greater breadth eliciting better protection. We analyzed TCR beta diversity and functional capacity for influenza-specific CD8(+) T cells expressing a single TCR alpha chain. Mice (A7) transgenic for the H2K(b)OVA(257-264)-specific V alpha 2.7 TCR were challenged with influenza to determine how fixing this "irrelevant" TCR alpha affects the "public" and restricted D(b)NP(366) (+)CD8(+) versus the "private" and diverse D(b)PA(224) (+)CD8(+) responses. Though both D(b)NP(366) (+)CD8(+) and D(b)PA(224) (+)CD8(+) sets are generated in virus-primed A7 mice, the constrained D(b)NP(366) (+)CD8(+) population lacked the characteristic, public TCRV beta 8.3, and consequently was reduced in magnitude and pMHC-I avidity. For the more diverse D(b)PA(224) (+)CD8(+) T cells, this particular forcing led to a narrowing and higher TCR beta conservation of the dominant V beta 7, though the responses were of comparable magnitude to C57BL/6J controls. Interestingly, although both the TCR beta diversity and the cytokine profiles were reduced for the D(b)NP(366) (+)CD8(+) and D(b)PA(224) (+)CD8(+) sets in spleen, the latter measure of polyfunctionality was comparable for T cells recovered from the infected lungs of A7 and control mice. Even "sub-optimal" TCR alpha beta pairs can operate effectively when exposed in a milieu of high virus load. Thus, TCR beta diversity is important for optimal TCR alpha beta pairing and function when TCR alpha is limiting.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / virology
  • Cells, Cultured
  • Cytokines / metabolism
  • Genes, T-Cell Receptor beta / genetics
  • Genes, T-Cell Receptor beta / immunology
  • Genetic Variation / immunology
  • H-2 Antigens / immunology
  • H-2 Antigens / metabolism
  • Histocompatibility Antigen H-2D
  • Influenza A virus / immunology*
  • Influenza A virus / pathogenicity
  • Lung / immunology*
  • Lung / pathology
  • Lung / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / virology
  • Ovalbumin / immunology
  • Peptide Fragments / immunology
  • Protein Multimerization / immunology
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism*
  • Viral Core Proteins / immunology

Substances

  • Cytokines
  • H-2 Antigens
  • H-2Kb protein, mouse
  • Histocompatibility Antigen H-2D
  • Peptide Fragments
  • Receptors, Antigen, T-Cell, alpha-beta
  • Viral Core Proteins
  • nucleoprotein (366-374), influenza virus
  • Ovalbumin