Development and maturation of natural killer cells

Abstract

Natural killer (NK) cells are innate lymphocytes that are critical for host protection against pathogens and cancer due to their ability to rapidly release inflammatory cytokines and kill infected or transformed cells. In the 40 years since their initial discovery, much has been learned about how this important cellular lineage develops and functions. We now know that NK cells are the founding members of an expanded family of lymphocyte known as innate lymphoid cells (ILC). Furthermore, we have recently discovered that NK cells can possess features of adaptive immunity such as antigen specificity and long-lived memory responses. Here we will review our current understanding of the molecular mechanisms driving development of NK cells from the common lymphoid progenitor (CLP) to mature NK cells, and from activated effectors to long-lived memory NK cells.

Figure 1. Stages of NK Cell Development

NK cells are derived from the CLP, which differentiates into a heterogeneous pre-NKP/ILCP population distinguished from the NKP by its expression of IL-7R and lack of CD122 expression. From the NKP, cells begin to express NK cell markers NK1.1 and NKp46, and as they further mature they acquire expression of DX5 (CD49b) and CD11b while losing expression of CD27. As NK cells mature they also gain functional competence, expressing lytic molecules and cytokines such as IFN-γ. Cell surface proteins are color coded by the stage in which they are first expressed. Loss of a specific cell surface marker after a given stage is indicated by parentheses in the stage immediately following.

Figure 2. Transcriptional Control of the NK Cell Lineage

A complex network of transcription factors governs the decision to adopt an innate or adaptive lymphocyte fate from the CLP. A simplified list of factors promoting the helper ILC, T cell, and B cell fates is shown. From the CLP, the indicated transcription factors drive cells to become NKP, immature NK cells (iNK) and mature NK cells (mNK). Factors promoting transition from the iNK to mNK stage are listed in two columns based on whether they are thought to be important earlier (left) or later (right) in NK cell maturation. Transcription factors are placed based upon where a defect or development arrest is seen in the knockout mouse when possible. Expression of the factors may occur before the indicated stage.

Figure 3. Regulation of NK Cell Function and Memory

Activated NK cells can secrete lytic molecules and IFN-γ. They can also proliferate in response to specific antigens and contract to form long-lived “memory” NK cells. Different cytokines (blue), transcription factors (purple), and other molecules (red) govern each of these distinct NK cell functions.