PT Unknown
AU Jenckel, A
TI The role of the actin-regulatory proteins Coronin 1A and Coronin 1B in the regulation of natural killer cell development and function
PY 2014
PU Christian-Albrechts-Universität zu Kiel
WP https://macau.uni-kiel.de/receive/diss_mods_00013975
LA en
DE natural killer cells; NK cells; Coronin; Coronin 1A; Coronin 1B; natürliche Killerzellen; NK-Zellen
AB NK cells play an important role in the clearance of viral and intracellular bacterial infections as well as in the elimination of tumor cells and have also been implicated in the regulation of other immune cells. Recent work demonstrates a crucial role of actin cytoskeletal-activities in controlling NK cell function. In eukaryotic cells, the maintenance of the actin cytoskeleton and its quick remodeling in response to various stimuli is orchestrated by a cohort of actin-associated proteins. Coronin proteins are part of this complex network of actin-regulatory proteins and, as such, have been implicated in various actin-mediated cellular activities in different cellular systems. However, the role of coronins in the control of NK cell functions is yet unknown.
In this thesis, I provide genetic evidence for an important role of two mammalian coronins, coronin 1a (Coro1a) and coronin 1b (Coro1b), in the regulation of NK cell development and function. By utilizing gene deficient mice I could demonstrate that the loss of Coro1a-function was directly linked to dysregulated F-actin organization in NK cells. While Coro1a-/- mice had normal numbers of peripheral NK cells, Coro1a-/- NK cells generally were of a more immature phenotype compared to wild type counterparts. The impaired NK cell maturation in Coro1a-/- mice was additionally associated with developmental alterations in the bone marrow. Although the single loss of Coro1b-function did not affect NK cell development and maturation, the immature phenotype of Coro1a-/- NK cells was further augmented by the additional loss of Coro1b. In vitro, IL-15 expanded Coro1a-/- and Coro1a-/-Coro1b-/- NK cells exhibited a comparable maturation status as wild type NK cells, but showed clear defects in central NK cell functions like killing of tumor cells, chemokine induced migration and cytokine secretion. The decreased cytotoxicity of Coro1a-/- and Coro1a-/-Coro1b-/- NK cells was associated with an impaired polarization of cytolytic granules and a reduced NK cell degranulation, whereas no major defects were found in early steps of the cytolytic response, including the formation of the cytolytic synapse and the consequent activation of NK cells. Thus, distinct actin associated processes involved in NK cell activities have different requirements on coronin proteins and the actin cytoskeleton. 
In conclusion, this study expands our knowledge on the function of actin-regulatory coronin proteins, by demonstrating that they do not only regulate known actin-dependent processes in NK cells, such as cell migration and cytotoxic granule release, but also control NK cell development. As coronin proteins and actin regulation are highly conserved between mice and man, the results obtained from this study are relevant for the human system. Thus, defective NK cell responses may contribute to the clinical symptoms observed in SCID patients with an inborn defect of Coro1a.
PI Kiel
ER