Cell-mediated immunity to flavivirus infections

<p>NK cells and T cells constitute a major part of the cell-mediated immune system and play important roles in the host defense against viral infections. Most current knowledge of cell-mediated immune responses to primary acute viral infections comes from murine models, while relatively less is known about human responses to, in particular, acute viral infections. In this thesis, the aim was to explore the early cell- mediated immune responses to acute viral infections in humans. The live attenuated yellow fever virus vaccine (YFV 17D) was used as a human in vivo model to study the dynamics and regulation of NK cell and T cell responses to the infection. In parallel, the NK cell and T cell responses to a natural acute infection caused by tick-borne encephalitis virus (TBEV) were studied. </p><p>Infection with YFV 17D induced activation of NK cells and T cells. An early activation in NK cell function, around one week post-vaccination, could be observed along with increased functions in response to target cells. A specific effector CD8 T cell response occurred that reached a peak of activation around two weeks post-vaccination, while CD4 T cell activation peaked earlier, around day 10, preceding that of CD8 T cells. The functional profile of the YFV 17D-specific CD8 T cell response changed in composition as it matured from an effector- to a memory-type response, and tended to become less polyfunctional during the course of this transition. In TBEV infected patients, NK cells were activated at the time of hospitalization. The activation subsequently decreased to healthy control levels. Simultaneous activation of CD8 and CD4 T cells occurred at one week following hospitalization and the TBEV-specific CD8 T cells showed a mono- functional profile that persisted over time. Furthermore, TBEV-specific CD8 T cells showed a distinct transcriptional profile in the effector phase of the T cell response. </p><p>Results presented in this thesis contribute to the understanding of the early T cell and NK cell responses in two human acute viral infections. In addition, they demonstrate that these two flaviviruses induce immune responses with different characteristics in infected humans.</p><h3>List of scientific papers</h3><p>I. Nicole Marquardt, Martin A. Ivarsson, Kim Blom, Veronica D. Gonzalez, Monika Braun, Karolin Falconer, Rasmus Gustafsson, Anna Fogdell- Hahn, Johan K. Sandberg and Jakob Michaëlsson, The Human NK Cell Response to Yellow Fever Virus 17D Is Primarily Governed by NK Cell Differentiation Independently of NK Cell Education. Journal of Immunology. 2015;195: 3262–3272. <br><a href="https://doi.org/10.4049/jimmunol.1401811">https://doi.org/10.4049/jimmunol.1401811</a><br><br> </p><p>II. Kim Blom and Monika Braun, Jolita Pakalniene, Sebastian Lunemann, Monika Enqvist, Laura Dailidyte, Marie Schaffer, Lars Lindquist, Aukse Mickiene, Jakob Michaëlsson, Hans-Gustaf Ljunggren, Sara Gredmark- Russ. Vivid Natural Killer Cell Response to Human Acute Tick-borne Encephalitis Virus Infection. [Manuscript]</p><p>III. Kim Blom, Monika Braun, Martin A. Ivarsson, Veronica D. Gonzalez, Karolin Falconer, Markus Moll, Hans-Gustaf Ljunggren, Jakob Michaëlsson and Johan K. Sandberg. Temporal Dynamics of the Primary Human T Cell Response to Yellow Fever Virus 17D As It Matures from an Effector- to a Memory-Type Response. Journal of Immunology, 2013, 190:2150-2158. <br><a href="https://doi.org/10.4049/jimmunol.1202234">https://doi.org/10.4049/jimmunol.1202234</a><br><br> </p><p>IV. Kim Blom, Monika Braun, Jolita Pakalniene, Laura Dailidyte, Vivien Béziat, Margit H. Lampen, Jonas Klingström, Nina Lagerqvist, Torbjörn Kjerstadius, Jakob Michaëlsson, Lars Lindquist, Hans-Gustaf Ljunggren, Johan K. Sandberg, Aukse Mickiene, Sara Gredmark-Russ. Specificity and Dynamics of Effector and Memory CD8 T Cell Responses in Human Tick-Borne Encephalitis Virus Infection. Plos Pathogens, 2015,11: e1004622–20. <br><a href="https://doi.org/10.1371/journal.ppat.1004622">https://doi.org/10.1371/journal.ppat.1004622</a><br><br> </p>