Molecular Mechanisms Directing Migration and Retention of Natural Killer Cells in Human Tissues

Abstract

A large body of data shows that Natural Killer (NK) cells are immune effectors exerting a potent cytolytic activity against tumors and virus infected cells. The discovery and characterization of several inhibitory and activating receptors unveiled most of the mechanisms allowing NK cells to spare healthy cells while selectively attacking abnormal tissues. Nevertheless, the mechanisms ruling NK cell subset recirculation among the different compartments of human body have only lately started to be investigated. This is particularly true for pathological settings such as tumors or infected tissues but also for para-physiological condition like pregnant human uterine mucosa. It is becoming evident that the microenvironment associated to a particular clinical condition can deeply influence the migratory capabilities of NK cells. In this review we describe the main mechanisms and stimuli known to regulate the expression of chemokine receptors and other molecules involved in NK cell homing to either normal or pathological/inflamed tissues, including tumors or organs such as lung and liver. We will also discuss the role played by the chemokine/chemokine receptor axes in the orchestration of physiological events such as NK cell differentiation, lymphoid organ retention/egress and recruitment to decidua during pregnancy.

Keywords: chemokines and chemokine receptors; migration and residency; natural killer cells; pregnancy; tumor and inflammation.

Figure 1

Circulating and tissues resident NK cells. (A) In human two main NK cell subsets, CD56bright and CD56dim, can be detected in peripheral blood (PB NK) having a different repertoire of chemokine receptors. Tissue resident (tr) NK cells share the expression of certain markers but express molecules typical of the hosting tissue.(B) large numbers of NK cells populate the decidua, particularly in the first trimester of pregnancy. Decidual NK cells have unique phenotypic and functional characteristics, which contribute to support nutrition of the fetus, ensure maternal-fetal tolerance and control viral infections. Prf1, perforin; KIRs, killer cell immunoglobulin-like receptors; SLT, secondary lymphoid tissues.

Figure 2

NK cells in tumor microenvironment. The tumor chemokine milieu presents a reduced expression of chemokines attracting CD56dim NK cells, and an increased expression of CXCL9/10, CCL5, and CXCL19/21 that drives the migration of CD56bright NK cells toward the stromal compartment and tertiary lymphoid tissue (TLS). Tumor cells and tumor-associated macrophages (TAM) release/activate TGF-β1 that decreases the capability of NK cells to recognize and kill targets and modify their chemokine receptor repertoire, hampering the recruitment of CD56dim NK cells and favoring that of poor cytolytic CD56bright. ActR, Activating receptors; GzmB, Granzyme B.

Figure 3

NK cells in inflamed tissues. Inflamed tissue produce chemokines (Chemerin, CX3CL1) that drive the migration of circulating CD56dim prf1high NK cells. Once in tissues they interact with DC and macrophages that, upon pathogen recognition, have begun to mature (mDC) or polarize toward a proinflammatory functional phenotype (M1). Maturing DC and M1-polarizing macrophages release immunostimulatory cytokines that induce NK cells to produce large amounts of IFN-γ (which potentiate phagocytes' functions) and to express IL-2Rα and CCR7, which drive their migration into secondary lymphoid organs (SLO). mDC migrated to SLO and DC-primed T cells producing IL-2 stimulate CD56dim NK cells and CD56bright NK cells that acquire a CD16^pos KIR^pos phenotype. ActR-L, Activating receptors ligands; iNKRs, MHC class I specific inhibitory receptors (KIRs, CD94/NKG2A); Chem, chemerin.