Hidden talents of natural killers: NK cells in innate and adaptive immunity

Abstract

Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells and producing immunoregulatory cytokines. Herein, we discuss recent studies that indicate that NK cells span the conventional boundaries between innate and adaptive immunity. For example, it was recently discovered that NK cells have the capacity for memory-like responses, a property that was previously thought to be limited to adaptive immunity. NK cells have also been identified in multiple tissues, and a subset of cells that specialize in the production of the T(H)17 cytokine IL-22, NK-22s, was recently described in mucosal-associated lymphoid tissue. Finally, we review work that shows that NK cells develop at sites that were traditionally thought to be occupied only by adaptive immune cells, including the thymus and lymph nodes.

Figure 1

Cytokine activation of NK cells induces the differentiation of memory-like cells with enhanced IFN-γ production. (A) Adoptive transfer model used to assess NK cell re-stimulation. Splenic NK cells are either activated using cytokines or control-treated, labelled with CFSE and transferred into Rag1-deficient hosts. This system allows the assessment of NK cell responses to re-stimulation. (B) Characterization of CFSE⁺ NK cells one week after transfer. Activated and control donor CFSE⁺ NK cells were easily identified by flow cytometry and did not constitutively produce IFN-γ in the absence of re-stimulation (cytometry gates are set on total NK cells). Activated NK cells proliferate after adoptive transfer, as evidenced by the dilution of CFSE, as compared to control NK cells. After re-stimulation with cytokines, significantly more of the previously activated donor NK cells produced IFN-γ compared to controls. The percentages indicate the proportion of IFN-γ⁺ NK cells in the CFSE⁺ or CFSE⁻ populations. CFSE, carboxyfluorescein succinimidyl ester; IFN-γ, interferon gamma; NK, natural killer.

Figure 2

Proposed mechanism of NK cell memory responses in immunity. Step 1. During an initial infection, NK cells provide a source of early IFN-γ in response to cytokines produced by macrophages and dendritic cells. Step 2. A fraction of activated NK cells might then differentiate into memory-like cells. Step 3. In the context of a new infection, memory-like NK cells would be activated again and trigger an enhanced IFN-γ response, possibly contributing to improved pathogen control. IFN-γ, interferon gamma; NK, natural killer.

Figure 3

Role of human NK-22 cells as a potential innate source of IL-22 for mucosal immunity. NK-22 cells express RORγt and home in on the lamina propria of the mucosa and on mucosal-associated lymphoid tissues through the CCR6–CCL20 interaction. Human NK-22 cells express adhesion molecules—such as CD96, JAML, and GPA33—which facilitate NK-22 epithelial cell interactions. Mucosal dendritic cells secrete IL-23 on interaction with microbial components, which stimulates NK-22 to secrete IL-22, IL-26, LIF and CCL20. IL-22, IL-26 and LIF promote epithelial cell survival, proliferation and secretion of the anti-inflammatory cytokine IL-10. CCL20 could facilitate the self-recruitment of NK-22 cells into the mucosa. CCL20, chemokine (C-C motif) ligand 20; CCR6, chemokine (C-C motif) receptor 6; GPA33, glycoprotein A33; JAML, junctional adhesion molecule-like; LIF, leukemia inhibitory factor; NK, natural killer; ROR, retinoid-related orphan receptor.

Megan A. Cooper

Marco Colonna

Wayne M. Yokoyama