Fig 1.

Hypothetical model of conditioning of NK cells by immune inflammatory cells and the effectors of connective tissue to modify NK cell phenotypic and functional properties in order to support differentiation of the cells and the resolution of inflammation. Hypothetical model of NK cell conditioning in the tumor microenvironment as well as in non-transformed immune inflammatory microenvironment is shown in this figure. Significant infiltration of immune effectors right beneath the epithelial layer can be seen in the connective tissue area where the immune inflammatory cells are likely to condition NK cells to lose cytotoxicity and gain the ability to secrete cytokines, a term which we have previously coined as split anergy in NK cells, and to support differentiation of the basal epithelial layer containing stem cells. NK cells are likely to encounter and interact with the other immune effectors such as monocytes or other myeloid-derived suppressor cells (MDSCs), and in tumor microenvironment with the tumor-associated macrophages (TAMs), or with connective tissue-associated fibroblasts (CAF) in order to be conditioned to form regulatory NK cells (NK_reg). NK cells may also directly interact with the stem cells at the base of the epithelial layer, in which case by eliminating their bound stem cells, they can become conditioned to support differentiation of other stem cells. In addition, bacteria through the binding to Toll like receptors can further aid in the generation of NK_reg. cells. All the above mentioned mechanisms may be operational during inflammatory processes in the tumor microenvironment or in healthy non-transformed inflammatory microenvironment. NK cell-differentiated epithelial cells will no longer be killed or induce cytokine secretion by the NK cells, therefore, resulting in the resolution of inflammation.