T Cell Modulation Laboratory, Department of Infection, Immunity and Biochemistry, Cardiff University School of Medicine, Cardiff, UK.
The human αβ TCR recombination machinery can rearrange and modify 176 genes into 1020 unique structures. Each human can house up to 1011 unique receptors in vivo. This massive repertoire pool is a core weapon of the cellular immune compartment and allows it to engage millions of never-before-seen threats with striking precision and specificity. It was originally thought that the production of this repertoire was a random event and the T cell responses to new viral threats largely stochastic between individuals. However two decades of research in the field has revealed this not to be the case. T cell responses engage viral antigens according to strict immunodominance hierarchies. Additionally, the dissection of clonotypes within each antigen-specificity often reveals biases in the TCR repertoire composition. Such TCR bias exists both within and between genetically unrelated individuals. Surprisingly, the underlying mechanisms behind both these phenomena are still largely theoretical and under constant investigation.
Why is the investigation of TCR repertoire dynamics important? Recent investigations in primate models suggests the initial “TCR choice” during primary infection can determine whether a virus establishes persistence or is cleared 1,2. Such descriptions of biological relevance remain to be established in humans. Information on basic TCR evolution during primary infection is, however, available in human HIV, HCMV and EBV infection. Here, acute EBV infection is the best studied of these models due to (i) the ubiquity of the virus in human populations (ii) the ability to outwardly detect primary infection through symptoms manifested as infectious mononucleosis (IM) and (iii) the ability to easily detect virus-specific T cells in the peripheral blood with multimers. First contact with EBV sees a massive CD8+ T cell burst in the periphery both during symptomatic 3 and asymptomatic infection 4. Strikingly, during acute infection, individual tetramer+ populations can comprise up to half the total CD8+ compartment. Generally, these tetramer+ populations are polyclonal in nature containing approximately half-a-dozen to a dozen clonotypes per specificity 5,6,7. However, this can be dependent on the donor and epitope studied. Very large tetramer+ expansions have a tendency to be oligoclonal. By and large the T cell contraction phase sees a roughly proportional shrinking across the complete virus-specific repertoire, and dominant clonotypes found in primary infection are usually present in memory. However, heavy or complete TCR repertoire remodelling during convalescence has been occasionally observed 7. It is presently unknown why this occurs. Into long-term memory, these viral-specific TCR repertoires appear to remain static for the life of an individual 8.
It remains to be said that, in humans, research into TCR evolution during primary infection is in its beginnings. Studies thus far have been small investigating only a few epitopes in a handful of individuals. Presently, a categorical understanding eludes us and will require larger approaches investigating the temporal TCR repertoire dynamics contained within the whole antiviral compartment, across many individuals. We also require more information on viruses with contrasting biologies, such as pathogens with variable genomes as well as those producing acute, reoccurring infection. Such labour is of merit since it may yield the ability to understand, predict and manipulate the TCR repertoire for the purposes of rational vaccine design and therapeutic intervention.
1. Price DA, West SM, Betts MR, et al. T cell receptor recognition motifs govern immune escape patterns in acute SIV infection. Immunity. 2004; 21:793-803.
2. Price DA, Asher TE, Wilson NA, et al. Public clonotype usage identifies protective Gag-specific CD8+ T cell responses in SIV infection. J Exp Med. 2009; 206:923-36.
3. Callan MF, N Steven, P Krausa, et al. Large clonal expansions of CD8+ T cells in acute infectious mononucleosis. Nat Med. 1996; 2:906‐911.
4. Elliott SL, Suhrbier A, Miles JJ, et al. Phase I trial of a CD8+ T-cell peptide epitope- based vaccine for infectious mononucleosis. J Virol. 2008; 82(3):1448-57.
5. Callan, MF, Fazou C, H. Yang, et al. CD8(+) T‐cell selection, function, and death in the primary immune response in vivo. J Clin Invest. 2000; 106:1251‐1261.
6. Silins SL, Cross SM, Elliott SL, et al. Development of Epstein-Barr virus-specific memory T cell receptor clonotypes in acute infectious mononucleosis. J Exp Med. 1996; 1;184(5):1815-24
7. Annels NE, Callan MF, Tan L, et al. Changing patterns of dominant TCR usage with maturation of an EBV-specific cytotoxic T cell response. J Immunol. 2000; 1;165(9):4831-41.
8. Miles JJ, Silins SL, Brooks AG, et al. T-cell grit: large clonal expansions of virus- specific CD8+ T cells can dominate in the peripheral circulation for at least 18 years. Blood. 2005; 15;106(13):4412-3.
This editorial was originally published in ProImmune’s December 2010 Newsletter