Pro-Inflammatory Cytokines Control The Anti-Viral Nk Cell Response.

Although natural killer (NK) cells are considered part of the innate immune system, recent studies have demonstrated the capability of virus-specific NK cells to become long-lived and contribute to potent recall responses similar to T and B cells. The precise signals that promote the generation of a long-lived NK cell response are largely undefined. This dissertation investigates the role of pro-inflammatory cytokines interleukin (IL)-12, IL-18, and type I IFN on the NK cell response during mouse cytomegalovirus (MCMV) infection. We demonstrate that IL-12 and its signaling component STAT4 are indispensible for MCMV-specific NK cell expansion and generation of “memory” NK cells in lymphoid and non-lymphoid tissues. Furthermore, IL-12 and STAT4 signaling in activated NK cells increased the expression of the adaptor protein MyD88, which mediates signaling downstream of the IL-18 receptor, and T-box transcription factor T-bet. During MCMV infection, NK cells required IL-18 receptor and MyD88 for optimal primary expansion, but not recall responses. In addition, NK cell-specific deletion of T-bet or Eomes crippled the anti-viral NK cell response. Lastly, we show type I IFN and STAT1 signaling protects NK cells form NKG2D-mediated killing, thus promoting a robust antiviral NK cell response. This work highlights the complex, non-redundant, and stage-specific role of pro-inflammatory cytokines and transcription factors on the NK cell response

Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide

Type I interferon (IFN) is crucial in host antiviral defense. Previous studies have described the pleiotropic role of type I IFNs on innate and adaptive immune cells during viral infection. Here, we demonstrate that natural killer (NK) cells from mice lacking the type I IFN-α receptor (Ifnar(−/−)) or STAT1 (which signals downstream of IFNAR) are defective in expansion and memory cell formation after mouse cytomegalovirus (MCMV) infection. Despite comparable proliferation, Ifnar(−/−) NK cells showed diminished protection against MCMV infection and exhibited more apoptosis compared with wild-type NK cells. Furthermore, we show that Ifnar(−/−) NK cells express increased levels of NK group 2 member D (NKG2D) ligands during viral infection and are susceptible to NK cell–mediated fratricide in a perforin- and NKG2D-dependent manner. Adoptive transfer of Ifnar(−/−) NK cells into NK cell–deficient mice reverses the defect in survival and expansion. Our study reveals a novel type I IFN–dependent mechanism by which NK cells evade mechanisms of cell death after viral infection

Proinflammatory cytokine signaling required for the generation of natural killer cell memory

Although natural killer (NK) cells are classified as innate immune cells, recent studies demonstrate that NK cells can become long-lived memory cells and contribute to secondary immune responses. The precise signals that promote generation of long-lived memory NK cells are unknown. Using cytokine receptor-deficient mice, we show that interleukin-12 (IL-12) is indispensible for mouse cytomegalovirus (MCMV)-specific NK cell expansion and generation of memory NK cells. In contrast to wild-type NK cells that proliferated robustly and resided in lymphoid and nonlymphoid tissues for months after MCMV infection, IL-12 receptor–deficient NK cells failed to expand and were unable to mediate protection after MCMV challenge. We further demonstrate that a STAT4-dependent IFN-γ–independent mechanism contributes toward the generation of memory NK cells during MCMV infection. Understanding the full contribution of inflammatory cytokine signaling to the NK cell response against viral infection will be of interest for the development of vaccines and therapeutics

Proapoptotic Bim regulates antigen-specific NK cell contraction and the generation of the memory NK cell pool after cytomegalovirus infection.

Apoptosis is critical for the elimination of activated lymphocytes after viral infection. Proapoptotic factor Bim (Bcl2l11) controls T lymphocyte contraction and the formation of memory T cells after infection. Natural killer (NK) cells also undergo antigen-driven expansion to become long-lived memory cells after mouse cytomegalovirus (MCMV) infection; therefore, we examined the role of Bim in regulating the MCMV-driven memory NK cell pool. Despite responding similarly early after infection, Bcl2l11(-/-) Ly49H(+) NK cells show impaired contraction and significantly outnumber wild-type (WT) cells after the expansion phase. The inability to reduce the effector pool leads to a larger Bcl2l11(-/-) NK memory subset, which displays a less mature phenotype (CD11b(lo), CD27(+)) and lower levels of NK cell memory-associated markers KLRG1 and Ly6C. Bcl2l11(-/-) memory NK cells demonstrate a reduced response to m157-mediated stimulation and do not protect as effectively as WT memory NK cells in an MCMV challenge model. Thus, Bim-mediated apoptosis drives selective contraction of effector NK cells to generate a pool of mature, MCMV-specific memory cells

Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide.

Type I interferon (IFN) is crucial in host antiviral defense. Previous studies have described the pleiotropic role of type I IFNs on innate and adaptive immune cells during viral infection. Here, we demonstrate that natural killer (NK) cells from mice lacking the type I IFN-α receptor (Ifnar(-/-)) or STAT1 (which signals downstream of IFNAR) are defective in expansion and memory cell formation after mouse cytomegalovirus (MCMV) infection. Despite comparable proliferation, Ifnar(-/-) NK cells showed diminished protection against MCMV infection and exhibited more apoptosis compared with wild-type NK cells. Furthermore, we show that Ifnar(-/-) NK cells express increased levels of NK group 2 member D (NKG2D) ligands during viral infection and are susceptible to NK cell-mediated fratricide in a perforin- and NKG2D-dependent manner. Adoptive transfer of Ifnar(-/-) NK cells into NK cell-deficient mice reverses the defect in survival and expansion. Our study reveals a novel type I IFN-dependent mechanism by which NK cells evade mechanisms of cell death after viral infection

Surface deformation resulting from subduction and slab detachment

Convergence of lithospheric plates is accommodated at active margins by one plate moving beneath the other into the Earth's mantle. Changes in this subduction process may cause variations in the topography of the Earth's surface near a convergent plate margin. The focus of this thesis lies on surface displacements which occur during ongoing subduction and in the final stages of a subduction process. During continuing subduction, surface displacements may, for example, be due to changes in buoyancy or plate velocity. In the last phase of a subduction process, surface uplift may result from detachment of subducted lithosphere from the lithosphere at the surface. This study was motivated by indications of slab detachment in regional tomographic images of the Mediterranean region. In general, study of the dynamics of subduction may add to understanding the origin of processes at the Earth's surface, for example, the formation of mountains and basins. Vice versa, analysis of surface data may contribute to insight in the physics of subduction