The identification of the specific DC subsets providing a critical role in presenting influenza antigens to naïve T cell precursors remains contentious and under considerable debate. Here we show that CD8+ T lymphocyte (TCD8+) responses are severely hampered in C57BL/6 mice deficient in the transcription factor Batf3 after intranasal challenge with influenza A virus (IAV). This transcription factor is required for the development of lymph node resident CD8+ and migratory CD103+CD11b− DCs and we found both of these subtypes could efficiently stimulate anti-IAV TCD8+. Using a similar ex vivo approach, many publications on this subject matter excluded a role for resident, non-migratory CD8+ DC. We postulate the differences reported can partially be explained by how DC are phenotyped, namely the use of MHC class II to segregate subtypes. Our results show that resident CD8+ DC upregulate this marker during IAV infection and we advise against its use when isolating DC subtypes.
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.
The disassembly of apoptotic cells into small membrane-bound vesicles termed apoptotic bodies (ApoBDs) is a hallmark of apoptosis; however, the functional significance of this process is not well defined. We recently discovered a new membrane protrusion (termed beaded apoptopodia) generated by apoptotic monocytes which fragments to release an abundance of ApoBDs. To investigate the function of apoptotic monocyte disassembly, we used influenza A virus (IAV) infection as a proof-of-concept model, as IAV commonly infects monocytes in physiological settings. We show that ApoBDs generated from IAV-infected monocytes contained IAV mRNA, protein and virions and consequently, could facilitate viral propagation in vitro and in vivo, and induce a robust antiviral immune response. We also identified an antipsychotic, Haloperidol, as an unexpected inhibitor of monocyte cell disassembly which could impair ApoBD-mediated viral propagation under in vitro conditions. Together, this study reveals a previously unrecognised function of apoptotic monocyte disassembly in the pathogenesis of IAV infections.
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