IL-33 Receptor ST2 Amplifies the Expansion of NK Cells and Enhances Host Defense during Mouse Cytomegalovirus Infection

Abstract

Natural killer (NK) cells provide important host defense against viruses and can differentiate into self-renewing memory NK cells after infection, alloantigen stimulation, and cytokine stimulation. Here, we investigated the role of the IL-33 receptor ST2 in the differentiation of NK cells during mouse cytomegalovirus (MCMV) infection. Although ST2-deficient (Il1rl1−/−) Ly49H+ NK cells develop normally and differentiate into memory cells after MCMV infection, naïve and memory Il1rl1−/− Ly49H+ NK cells exhibited profound defects in MCMV-specific expansion, resulting in impaired protection against MCMV challenge. Additionally, IL-33 enhanced m157 antigen-specific proliferation of Ly49H+ NK cells in vitro. Thus, an IL-33-ST2 signaling axis in NK cells contributes to host defense against MCMV.

Natural killer cell memory in infection, inflammation and cancer

“…In this study, neutralization of IL-12, but not IL-15 or IL-18, or blockade of type I IFN receptor in the PBMC and HCMV-infected fibroblast co-cultures significantly decreased expansion of the CD94-NKG2C + NK cell subset. Accordingly, in the MCMV model, IL-15 was dispensable for the expansion and memory formation of LY49H + NK cells 49 , but both IL-18 and IL-33 contributed to the expansion of MCMV-specific NK cells, but not to the generation of memory 50,51 . Of note, humans with genetic defects in IL-12 production were not reported to have impaired resistance to HCMV 52 , indicating the existence of redundant pathways for HCMV immunity.…”

Memory responses of natural killer cells

“…In contrast, the ability to sense type I IFN is critical for memory NK cell generation, as the IFNAR/STAT1 signaling pathway protects proliferating NK cells from being killed by other NK cells (in a process known as ‘fratricide’) during the expansion phase [44]. Two members of the IL-1 family of cytokines, IL-18 and IL-33, and their downstream signaling molecule MyD88, are also important for the optimal expansion of MCMV-specific effector NK cells, but are dispensable for the recall response of memory cells to MCMV [35, 45]. …”

Sweet Is the Memory of Past Troubles: NK Cells Remember

“…The proliferation phase of Ly49H + NK cells following MCMV infection is dependent on IL-12 and STAT4 signaling (Sun et al 2012); on the other hand, IL-15, which is known to be a key NK cell survival factor, was shown to be more critical during the maintenance phase (Firth et al 2013). IL-18 (Madera and Sun 2015) and IL-33 (Nabekura 2015) are required for an optimal primary response of NK cells to MCMV, but are not required for the generation or maintenance of the memory NK cell population. Moreover, IL-18 and IL-33 are not required for the recall response of Ly49H + memory NK cells (Madera and Sun 2015;Nabekura 2015).…”

“…IL-18 (Madera and Sun 2015) and IL-33 (Nabekura 2015) are required for an optimal primary response of NK cells to MCMV, but are not required for the generation or maintenance of the memory NK cell population. Moreover, IL-18 and IL-33 are not required for the recall response of Ly49H + memory NK cells (Madera and Sun 2015;Nabekura 2015). A role for microRNAs in NK cell memory has also been uncovered, as miRNA-155 drives suppression of both Noxa and SOCS1 to allow for proliferation and appropriate expansion of the antigen-specific NK cell subset following MCMV infection (Zawislak et al 2013).…”