Abstract
Multi-cellular cluster formation of natural killer (NK) cells occurs during in vivo priming and potentiates their activation to IL-2. However, the precise mechanism underlying this synergy within NK cell clusters remains unclear. We employed lymphocyte-laden microwell technologies to modulate contact-mediated multi-cellular interactions among activating NK cells and to quantitatively assess the molecular events occurring in multi-cellular clusters of NK cells. NK cells in social microwells, which allow cell-to-cell contact, exhibited significantly higher levels of IL-2 receptor (IL-2R) signaling compared with those in lonesome microwells, which prevent intercellular contact. Further, CD25, an IL-2R α chain, and lytic granules of NK cells in social microwells were polarized toward MTOC. Live cell imaging of lytic granules revealed their dynamic and prolonged polarization toward neighboring NK cells without degranulation. These results suggest that IL-2 bound on CD25 of one NK cells triggered IL-2 signaling of neighboring NK cells. These results were further corroborated by findings that CD25-KO NK cells exhibited lower proliferation than WT NK cells, and when mixed with WT NK cells, underwent significantly higher level of proliferation. These data highlights the existence of IL-2 trans-presentation between NK cells in the local microenvironment where the availability of IL-2 is limited.
Highlights
Formation of multi-cellular clusters can promote interactions among different cell types, and increase the probability of interactions among identical cells, or homotypic cell-to-cell interactions[16,17]
We uncover the existence of IL-2 trans-presentation within multi-cellular Natural killer (NK) clusters that synergizes with IL-2R signaling at the membrane proximal step
Considering that NK cell priming in vivo occurs in the presence of abundant natural Tregs, which consume considerable IL-2 by constitutively expressing CD25, such a CD25/IL-2 trans-presentation mechanism secures the IL-2 from shared limited resources
Summary
Formation of multi-cellular clusters can promote interactions among different cell types, and increase the probability of interactions among identical cells, or homotypic cell-to-cell interactions[16,17]. Characterization of phosphorylation, expression and polarization of signaling molecules within multi-cellular clusters of NK cells revealed that IL-2 captured by IL-2R on one NK cell could trigger IL-2R signaling of other surrounding NK cells through intercellular contact. This IL-2 trans-presentation within multi-cellular clusters of NK cells can serve as an important strategy for NK cells to maximally utilize IL-2, which can be a limited resource during the early stages of immune responses because of the competition among many other types of lymphocytes
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