Reproducible selection of high avidity CD8+ T-cell clones following secondary acute virus infection - PubMed (original) (raw)
Reproducible selection of high avidity CD8+ T-cell clones following secondary acute virus infection
Tania Cukalac et al. Proc Natl Acad Sci U S A. 2014.
Abstract
The recall of memory CD8(+) cytotoxic T lymphocytes (CTLs), elicited by prior virus infection or vaccination, is critical for immune protection. The extent to which this arises as a consequence of stochastic clonal expansion vs. active selection of particular clones remains unclear. Using a parallel adoptive transfer protocol in combination with single cell analysis to define the complementarity determining region (CDR) 3α and CDR3β regions of individual T-cell receptor (TCR) heterodimers, we characterized the antigen-driven recall of the same memory CTL population in three individual recipients. This high-resolution analysis showed reproducible enrichment (or diminution) of particular TCR clonotypes across all challenged animals. These changes in clonal composition were TCRα- and β chain-dependent and were directly related to the avidity of the TCR for the virus-derived peptide (p) + major histocompatibility complex class I molecule. Despite this shift in clonotype representation indicative of differential selection, there was no evidence of overall repertoire narrowing, suggesting a strategy to optimize CTL responses while safeguarding TCR diversity.
Keywords: antiviral immunity; clonal selection; influenza virus; memory CD8+ T cells; recall CD8+ T-cell response.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Fig. 1.
Consistent selection of TCRβ clonotypes following secondary virus infection. Individual memory phase (6–8 wk after infection) DbNP366+ TRBV13-1+ CD45.1+ CD8+ T cells were sorted from a sample of spleen. Remaining splenocytes (2–3 × 107 cells per mouse) were transferred into three sublethally irradiated (550 rad) recipient mice (CD45.2+). Recipient mice were infected (i.n.) 1 d later with ×31 influenza virus and, on day 8, individual DbNP366+ TRBV13-1+ CD45.1+ CD8+ T cells were sorted (A). Representative flow cytometry plots of sorted memory DbNP366+ TRBV13-1+ CD8+ T cells or acute recall DbNP366+ TRBV13-1+ CD45.1+ CD8+ T cells (B). TRBV13-1–specific nested single-cell RT-PCR was performed on sorted cells to determine CDR3β use. Plots represent the percentage contribution of individual TCRβ clonotypes to the total sequenced TCRβ population, shown for one representative experiment of a total of six (C). n, number of sequences.
Fig. 2.
Consistent selection of TCRα and TCRαβ clonotypes following secondary virus infection. The adoptive transfer and infection strategy outlined in Fig. 1_A_ was used to simultaneously determine TRB13-1 and TRAV use for the experiments outlined in Fig. 1_C_. Plots represent the percentage contribution of individual TCRα clonotypes to the total sequenced TCRα population, irrespective of CDR3β use (A). Plots represent the percentage contribution of individual TCRαβ clonotypes to the total sequenced TCRαβ population (B). n, number of sequences. Tables contain the 95% CI for each designated clonotype contribution, and P values test the hypothesis that a given sequence in donor and recipient populations comes from the same underlying distribution.
Fig. 3.
Altered clonal prevalence correlates with TCR avidity. 293T cells were transfected with MSCV vectors encoding the CD3γδε and ζ chains (GFP) and either of the designated DbNP366-specific TCRs, identified by expression of GFP or AmCyan. After 48 h, cells were stained with anti–TCRβ-APC and DbNP366-PE tetramer. GFP+ (RVSG/SGGG) or GFP+AmCyan+ (RANS/SGGA) cells were gated for uniformly high TCR expression (A). A representative and mean level of tetramer binding (MFI) is shown for triplicate samples of TCRhi cells (B), and the rate of tetramer dissociation in the presence of an anti-H2Db antibody was determined on triplicate samples of transfected cells (C).
Fig. 4.
Reversion of TCRβ clonal prevalence in secondary memory. The strategy outlined in Fig. 1_A_ was modified such that blood was analyzed 8 d after secondary infection, and splenocytes were analyzed 60 d after infection (second memory). Plots represent the percentage contribution of individual TCRαβ clonotypes to the total sequenced TCRαβ population for primary memory (A), acute recall (B), and secondary memory (C) populations. n, number of paired CDR3αβ amino acid sequences obtained. P values test the hypothesis that a given sequence in donor and recipient populations comes from the same underlying distribution. Shown is one of two representative experiments.
Fig. 5.
No evidence of global narrowing of TCR repertoire diversity in acute recall or secondary memory. TCRβ clonotypic diversity within primary memory, recall, and secondary memory populations was measured using Simpson’s diversity index. Symbols represent populations derived from the same experiment. Lines connect related populations.
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