Reversal in the Immunodominance Hierarchy in Secondary CD8+ T Cell Responses to Influenza A Virus: Roles for Cross-Presentation and Lysis-Independent Immunodomination

Abstract

Immunodominance is a central feature of CD8+ T cell (TCD8+) responses to pathogens, transplants, and tumors. Determinants occupy a stable position in an immunodominance hierarchy (α-, β-, etc.) defined by the frequencies of responding TCD8+. In this paper, we study the mechanistic basis for place-swapping between α- (acid polymerase (PA)224–233) and β-determinants (nuclear protein 366–374) in primary vs secondary anti-influenza A virus (IAV) responses in mice. This phenomena was recently correlated with the inability of IAV-infected nondendritic cells (DCs) to generate PA224–233, and it was proposed that secondary TCD8+ are principally activated by IAV-infected epithelial cells, while primary TCD8+ are activated by IAV-infected DCs. In this study, we show that the inability of non-DCs to generate PA224–232 is relative rather than absolute, and that the preferential use of cross-priming in secondary anti-IAV responses can also account for the revised hierarchy. We further show that immunodomination of PA224–233-specific TCD8+ by nucleoprotein 366–374-specific TCD8+ plays a critical role in the phenomena, and that this is unlikely to be mediated by TCD8+ lysis of APCs or other cells.

Compartmentalized MHC class I antigen processing enhances immunosurveillance by circumventing the law of mass action

“…FAP, SIIN, and RGY bind to K b with near-identical affinities, whereas SSL binds to D b with a higher affinity than LSL, which binds with slightly higher affinity than ASN. [Note that using a different assay, these three peptides were found to bind to D b with much closer affinities (8).] Infection of L-K b or L-D b cells with rVVs over a 100-fold range in multiplicity of infection (MOI) revealed a discrepancy between the expression of Venus or mCherry and that of class I peptide complexes (CPCs) for each of the four peptides evaluated (Fig.…”

Immunoproteasome-Deficient Mice Mount Largely Normal CD8+ T Cell Responses to Lymphocytic Choriomeningitis Virus Infection and DNA Vaccination

“…We show that the gp276-specific CD8 ϩ T cell population becomes more dominant during a normal recall response (e.g., secondary LCMV infection), and that this phenomenon is present in both WT and LMP-deficient mice. Thus, dynamic changes in the immunodominance hierarchies of LCMV-specific CD8 ϩ T cell responses can occur independently of immunoproteasomes and may be a consequence of T cell expansion and immunodomination, as has been suggested for influenza virus infection (28). Fourth, the authors concluded that the LMP proteins could determine the dominance hierarchy during virus infection, whereas we conclude that immunoproteasomes play little, if any, role in regulating the character or intensity of the CD8 ϩ T cell response to normal LCMV infection.…”

“…The relative abundances of different epitope-specific populations can change after secondary virus infection (26,27); several explanations have been proposed, including differential Ag presentation, cross-presentation, and immunodomination (23,28,29). In this study we asked whether immunoproteasome deficiency might contribute to the phenomenon.…”

Cross-protective immunity against influenza pH1N1 2009 viruses induced by seasonal influenza A (H3N2) virus is mediated by virus-specific T-cells

“…It has been shown that in the absence of a response to the dominant NP 366-374 epitope caused by mismatch of the amino acid sequence, the PA 224-233 epitope gains immunodominance (Chen et al, 2004). Whether or not PA 224-233 -specific CD8 + T-cells are protective is still a matter of debate (Crowe et al, 2003;Chen et al, 2004). Thus, the observed protection did not correlate with NP 366-374 -specific CD8 + T-cell responses but may be afforded by PA 224-233 -specific CD8 + T-cells and, most probably, by those to other viral epitopes.…”