Activation status of NK cells mediates distinct T cell responses

Problem: NK cells have recently been shown to have phenotypic features of CD11c+ dendritic cells (DCs). However, the precise factors that regulate such attributes in NK cells and their significance in T cell response are poorly understood. Methods: In order to examine the DC-like phenotypic and functional features of CD3-NK1.1+ NK cells, we created homozygous B6.CD11c-GFP reporter mice, in which the expression of CD11c is genetically linked to co-expression of GFP and diphtheria toxin receptor (DTR). Furthermore, we generated T cell receptor-transgeneic B6.OTIIa-Foxp3-GFP-knockin mice to study the role of NK cells as antigen presenting cells (APCs) in T cell response in vitro. Results: Using a polychromatic approach we found that NK cells in naive B6 mice express low levels of CD11c, B220, CD86, and MHCII, in line with recent reports. Importantly, further studies in wild-type B6 and B6.CD11c-GFP mice showed that those markers are upregulated on NK cells upon activation with IL-15 or TLR ligands (i.e. PolyI:C, ODN1668) in vivo. Thus, we hypothesized that NK cells by themselves may directly function as APCs that regulate antigen-specific T cell response in vitro. Using our OTIIa-Foxp3-GFP-knockin model, we found that naive NK cells induce modest proliferation of GFP-T effector cells (Teffs) at levels comparable to plasmacytoid DCs (pDCs), whereas activated NK cells largely failed to induce Teffs expansion, due to the killing of proliferating Teffs in a Perforin-dependent fashion. Intriguingly, we also found that naive NK cells are powerful inducers of GFP+ regulatory T cells (iTregs) when compared to pDCs and conventional DCs; whereas activated NK cells largely prevent the generation of iTregs in a Perforin-and IFN-γ-dependent manner. Conclusions: NK cells play a dichotomous role in T cell response contingent on their activation status, giving them a novel role in directly regulating peripheral T cell homeostasis in autoimmunity and transplantation.