JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation

Abstract

Natural Killer (NK) cells are cytotoxic lymphocytes of the innate immune system and play a critical role in anti-viral and anti-tumor responses. NK cells develop in the bone marrow from hematopoietic stem cells (HSCs) that differentiate through common lymphoid progenitors (CLPs) to NK lineage-restricted progenitors (NKPs). The orchestrated action of multiple cytokines is crucial for NK cell development and maturation. Many of these cytokines such as IL-2, IL-7, IL-12, IL-15, IL-21, IL-27, and interferons (IFNs) signal via the Janus Kinase / Signal Transducer and Activator of Transcription (JAK/STAT) pathway. We here review the current knowledge about these cytokines and the downstream signaling involved in the development and maturation of conventional NK cells and their close relatives, innate lymphoid cells type 1 (ILC1). We further discuss the role of suppressor of cytokine signaling (SOCS) proteins in NK cells and highlight their potential for therapeutic application.

Keywords: ILC1; JAK; NK cell; SOCS; STAT; cytokine; development; maturation.

Figure 1

Schematic representation of the canonical JAK/STAT signaling pathway. The JAK/STAT pathway transmits extracellular cytokine signals to the nucleus. Upon binding of a cytokine to its transmembrane receptor, receptor-associated JAKs are activated and phosphorylate STAT proteins. Activated STAT proteins translocate as either homo- or hetero-dimers to the nucleus and modulate target gene transcription. In a negative feedback loop, SOCS proteins are expressed and inhibit the JAK/STAT signaling cascade by suppressing JAK kinase activity, by competing with STAT proteins for binding to the receptor and/or by proteasomal degradation of the proteins.

Figure 2

Schematic overview of crucial cytokines in NK cell biology, their associated JAK and STAT proteins, exemplary target genes and biological effects. One cytokine can lead to the activation of several STAT proteins. STAT proteins predominantly activated by the respective cytokine are depicted in bold font; STAT proteins that have been reported to be activated to a lesser extent are depicted in light font. The details and references for distinct cytokine signaling cascades and the functional responses can be found in the corresponding sections of the main text.

Figure 3

The roles of distinct JAK/STAT and SOCS family members in NK cells. NK cell development, maturation and function are tightly regulated by a plethora of cytokines, which most prominently use the JAK/STAT pathway for their signal transduction. This figure summarizes the available literature about each member of the JAK/STAT signaling pathway and some of their negative regulators (SOCS1-3 and CIS), relevant upstream cytokines and the NK cell phenotypes observed in complete or conditional knockout mice. The individual cells are coded by color: compared to wild-type reduced (blue), unchanged (gray) or increased (red); blank cells indicate not determined yet. c, complete knockout mice; CIS, cytokine induced SH2-containing protein; CYTO, cytotoxicity; DEV, development; h, hematopoietic cell-restricted knockout mice; IFN, interferon; IL, interleukin; IFN-γ, IFN-γ production; JAK, Janus kinase; KO, knockout; MAT, maturation; MHC, major histocompatibility complex; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; TYK2, tyrosine kinase 2.