Reversal in the immunodominance hierarchy in secondary CD8+ T cell responses to influenza A virus: roles for cross-presentation and lysis-independent immunodomination.
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 (alpha-, beta-, etc.) defined by the frequencies of responding TCD8+. In this paper, we study the mechanistic basis for place-swapping between alpha- (acid polymerase (PA)(224-233)) and beta-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 PA(224-233), 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 PA(224-232) 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 PA(224-233)-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.
T Cell Laboratory, Ludwig Institute for Cancer Research, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.
Weisan
W
Chen
Ken
K
Pang
Kelly-Anne
KA
Masterman
Gina
G
Kennedy
Sameh
S
Basta
Nektaria
N
Dimopoulos
Felicita
F
Hornung
Mark
M
Smyth
Jack R
JR
Bennink
Jonathan W
JW
Yewdell
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D045142:Cross-Priming; D003602:Cytotoxicity, Immunologic; D007156:Immunologic Memory; D009980:Influenza A virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL