Increasing Viral Dose Causes a Reversal in CD8+ T Cell Immunodominance during Primary Influenza Infection due to Differences in Antigen Presentation, T Cell Avidity, and Precursor Numbers

Abstract

T cell responses are characterized by the phenomenon of immunodominance (ID), whereby peptide-specific T cells are elicited in a reproducible hierarchy of dominant and subdominant responses. However, the mechanisms that give rise to ID are not well understood. We investigated the effect of viral dose on primary CD8+ T cell (TCD8+) ID by injecting mice i.p. with various doses of influenza A virus and assessing the primary TCD8+ response to five dominant and subdominant peptides. Increasing viral dose enhanced the overall strength of the TCD8+ response, and it altered the ID hierarchy: specifically, NP366–374 TCD8+ were dominant at low viral doses but were supplanted by PA224–233 TCD8+ at high doses. To understand the basis for this reversal, we mathematically modeled these TCD8+ responses and used Bayesian statistics to obtain estimates for Ag presentation, TCD8+ precursor numbers, and avidity. Interestingly, at low viral doses, Ag presentation most critically shaped ID hierarchy, enabling TCD8+ specific to the more abundantly presented NP366–374 to dominate. By comparison, at high viral doses, TCD8+ avidity and precursor numbers appeared to be the major influences on ID hierarchy, resulting in PA224–233 TCD8+ usurping NP366–374 cells as the result of higher avidity and precursor numbers. These results demonstrate that the nature of primary TCD8+ responses to influenza A virus is highly influenced by Ag dose, which, in turn, determines the relative importance of Ag presentation, TCD8+ avidity, and precursor numbers in shaping the ID hierarchy. These findings provide valuable insights for future TCD8+-based vaccination strategies.

Functional Avidity–Driven Activation-Induced Cell Death Shapes CTL Immunodominance

“…Although the reciprocal influence between the Ag dose and the functional avidity of a responding T cell population is in line with other reports (33)(34)(35), we propose the existence of an AICD-driven inverse correlation between functional avidity and the establishment of the ID hierarchy. Therefore, this novel mechanism in the establishment of the ID restrains and opposes the expansion of high-avidity T cells in favor of lower-affinity populations.…”

“…In addition to the Ag dose and presentation (33,38), all of the factors impacting the fine balance between Ag and responding T cells (the immunization route (39), the biochemical nature of the immunogen [DNA versus peptide (40)], and possibly the persistence of the Ag (41) acquire even more importance when dealing with high-avidity T cells because of their proneness to AICD in an excess of stimulation.…”

The Influenza Virus–Specific CTL Immunodominance Hierarchy in Mice Is Determined by the Relative Frequency of High-Avidity T Cells

“…Thus, our results suggest that the impact of Ag load on CTL immunodominance may, in some circumstances, be subject to overriding influences. Indeed, a recent study has proposed that CTL immunodominance hierarchies are predominantly influenced by CTLp frequency and TCR avidity at high virus doses, and by Ag presentation when Ag is limiting (43). Our data are consistent with this idea in that, early in the response (days 4-6) when viral loads are relatively high, immunodominance hierarchies largely reflect naive CTLp frequencies.…”

Sizing up the key determinants of the CD8+ T cell response

“…Recent studies in vaccinia virus-or IAV-infected mice have, however, clearly demonstrated that CTL immunodomination occurs in endogenous primary CTL responses 69,70 . In these experiments, viral antigen dose was controlled by altering the route of infection, an approach that in turn limited the capacity of the challenge virus to either grow productively (in the case of IAV infection) 70 or to establish systemic infection (in the case of vaccinia virus infection) 69 .…”

“…In these experiments, viral antigen dose was controlled by altering the route of infection, an approach that in turn limited the capacity of the challenge virus to either grow productively (in the case of IAV infection) 70 or to establish systemic infection (in the case of vaccinia virus infection) 69 . Under these conditions of limited antigen availability, subdominant responses were selectively disadvantaged, whereas greater viral loads resulted in blunted (or abrogated) CTL immunodominance, supporting the notion that limiting antigen dose promotes immuno domination 63,69,70 .…”