Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion
Nicole L. La Gruta, William T. Rothwell, Tania Cukalac, Natasha G. Swan, Sophie A. Valkenburg, Katherine Kedzierska, Paul G. Thomas, Peter C. Doherty, Stephen J. Turner
Nicole L. La Gruta, William T. Rothwell, Tania Cukalac, Natasha G. Swan, Sophie A. Valkenburg, Katherine Kedzierska, Paul G. Thomas, Peter C. Doherty, Stephen J. Turner
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Research Article Immunology

Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion

Abstract

CD8+ T cell responses to viral infection are characterized by the emergence of dominant and subdominant CTL populations. The immunodominance hierarchies of these populations are highly reproducible for any given spectrum of virus-induced peptide-MHCI complexes and are likely determined by multiple factors. Recent studies demonstrate a direct correlation between naive epitope-specific CD8+ T cell precursor (CTLp) frequency and the magnitude of the response after antigen challenge. Thus, the number of available precursors in the naive pool has emerged as a key predictor of immunodominance. In contrast to this, we report here no consistent relationship between CTLp frequency and the subsequent magnitude of the immune response for 4 influenza virus–derived epitopes following intranasal infection of mice with influenza A virus. Rather, the characteristic, antigen-driven T cell immunodominance hierarchy was determined by the extent of recruitment from the available pool of epitope-specific precursors and the duration of their continued expansion over the course of the infection. These findings suggest possibilities for enhancing protective immune memory by maximizing both the size and diversity of typically subdominant T cell responses through rational vaccine design.

Authors

Nicole L. La Gruta, William T. Rothwell, Tania Cukalac, Natasha G. Swan, Sophie A. Valkenburg, Katherine Kedzierska, Paul G. Thomas, Peter C. Doherty, Stephen J. Turner

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Figure 1

Influenza epitope–specific immune magnitudes do not correlate with naive precursor frequencies.

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Influenza epitope–specific immune magnitudes do not correlate with naive...
(A) Naive B6 mice were infected i.n. with influenza virus and spleens harvested 7, 8, or 10 days later for analysis of CD8+ DbNP366-, DbPA224-, DbPB1-F262–, and KbNS2114-specific T cell responses. Shown are the mean total splenic numbers of CD8+tetramer+ cells for 4–5 mice ± SD. Results are representative of 2 independent experiments. (B) Representative dot plots of all DbNP366-, DbPA224-, DbPB1-F262–, and KbNS2114-specific CD8+ T cells detected from spleen and all major LNs of naive mice using a magnetic enrichment and staining procedure (as described in Methods). Values indicate the number of tetramer+CD62Lhi cells within the gate shown. (C) Total numbers of epitope-specific CD8+ cells identified from spleen and all major LNs in naive B6 mice or OTI TCR Tg mice. Symbols represent data from individual mice obtained in 4 independent experiments. Horizontal bars indicate mean values.