Impact of NKG2D signaling on T cell and NK cell function in cerebral ischemia
Final Report Abstract
Stroke is the second leading cause of death worldwide and one of the most common causes of long-term physical disability in adults. Despite its enormous relevance, the pathogenesis of stroke is still insufficiently understood. Post-stroke inflammation has been recognized for many years and particularly T and NK (natural killer) cells have been identified as essential drivers of the immune response. Recent studies implicated the immune response in disease progression using the immunodeficient Rag1-/- animal model that lacks functional T and B cells. However, remaining NK cells in Rag1-/- animals may influence the results of these studies and possible changes in the development and function of Rag1-/- NK cells have not yet been clarified. To address this issue, immunological phenotype, and functionality of NK cells from Rag1-/- and wild-type mice were characterized in the context of stroke. No differences were observed, emphasizing that NK cells should be considered when interpreting data from immune cell transfer models in experimental stroke. Therefore, identification of a more suitable transfer model to study the functional implications for NK cells in ischemic stroke development was needed. Including the NOD-Rag1nullIL2rgnull (NRG) mouse model, which is characterized by deficiency in T, B and NK cells, in vivo relevance of NK cells in disease progression was investigated. Antibody-mediated depletion of NK cells in Rag1-/- animals and NK cell transfer into NRG mice before stroke induction demonstrated a detrimental role of NK cells in the pathogenesis of stroke. Absence of NK cells were protective in experimental stroke, while the transfer of NK cells into NRG mice exacerbated stroke outcome. Based on these results, the second work aimed to understand the mechanism of NK cell-mediated tissue damage after ischemic injury. Blockade of the immunoreceptor NKG2D expressed on NK, NKT and subsets of T cells, implicated NKG2D signaling in stroke development. Upon receptor blockade, infarct volumes as well as neurological deficits were improved, and infiltrations of immune cell subsets decreased. Using adoptive transfer of different NKG2D-expressing lymphoid immune cell subsets in immunodeficient mice with and without receptor blockade, NK cells and cytotoxic CD8+ T cells were shown to predominantly mediate the detrimental, NKG2D-dependent effect on stroke progression. Activation of CD8+ T cells via the NKG2D receptor is direct-stimulatory without the involvement of the T cell receptor and induces cytotoxic effector functions. Expression and localization of NKG2D ligands in murine and human brain tissue further characterized the NKG2D signaling pathway after stroke. Detection of the NKG2D receptor and its ligands in brain samples from stroke patients underlines the relevance of the preclinical observations. With its expression on stroke relevant immune cell types and the possible pharmacological modulation of the pathway, NKG2D is a promising target in the context of stroke. This work provides a mechanistic insight in NK cell-mediated tissue damage and contributes to a better understanding of the complex immune response after ischemic stroke.
Publications
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Natural Killer Cells Are Present in Rag1−/− Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke. Translational Stroke Research, 13(1), 197-211.
Rolfes, Leoni; Ruck, Tobias; David, Christina; Mencl, Stine; Bock, Stefanie; Schmidt, Mariella; Strecker, Jan-Kolja; Pfeuffer, Steffen; Mecklenbeck, Andreas-Schulte; Gross, Catharina; Gliem, Michael; Minnerup, Jens; Schuhmann, Michael K.; Kleinschnitz, Christoph & Meuth, Sven G.
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Impact of NKG2D Signaling on Natural Killer and T‐Cell Function in Cerebral Ischemia. Journal of the American Heart Association, 12(12).
David, Christina; Ruck, Tobias; Rolfes, Leoni; Mencl, Stine; Kraft, Peter; Schuhmann, Michael K.; Schroeter, Christina B.; Jansen, Robin; Langhauser, Friederike; Mausberg, Anne K.; Fender, Anke C.; Meuth, Sven G. & Kleinschnitz, Christoph
