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Natural killer (NK) cells are innate effector cells with critical roles not only in tumor immunosurveillance and viral immunity, but also in bacterial and fungal infections. Toll‐like receptor 2 (TLR2) can be important in the early and sustained immune responses to pathogens and tumors through the induction of cytokines and chemokines that recruit and activate immune effector cells. We investigated the role of TLR2 activation in NK cell recruitment with a view to informing approaches to induce or regulate peritoneal NK cell responses therapeutically. Peritoneal injection of TLR2 activators, including peptidoglycan and the lipopeptides FSL‐1 and Pam3CSK4, resulted in NK cell recruitment after 16 h with increased NK cell numbers maintained for 48 h. TLR2 activators induced large amounts of CCR2 ligands, but much smaller amounts of CCR5 and CXCR3 ligands. Consistent with this observation, NK cell migration was abrogated in CCR2‐deficient mice after peritoneal FSL‐1 injection. Adoptive transfer of CCR2‐deficient NK cells prior to peritoneal FSL‐1 activation confirmed a cell‐intrinsic component of CCR2‐mediated NK cell migration. TLR2 activation did not induce an activated NK cell phenotype, but significant changes included an increase in the KLRG1+ subset and decreased NKG2D expression. Although not activated in vivo, peritoneal NK cells could be activated by interleukin (IL)‐12 and IL‐18 ex vivo to express CD69 and interferonγ. These data demonstrate that TLR2‐mediated immune activation is a potent inducer of NK cell recruitment via a CCR2‐dependent mechanism and that NK cells recruited by this mechanism can respond to additional signals to exert effector cell functions., In this study, we showed that induction of inflammation in the peritoneal cavity by Toll‐like receptor 2 (TLR2) agonists induces chemokine production with very high levels of the CCR2 ligands CCL2 and CCL7. Natural killer (NK) cells are recruited to the peritoneum after TLR2‐induced inflammation in a CCR2‐dependent manner, but do not acquire an activated phenotype. Recruited NK cells can be activated by interleukin (IL)‐12 and IL‐18 to express CD69 and interferonγ.

Histamine receptor 2 (H2R) blockade is commonly used in patients with gastric, duodenal ulcers or gastroesophageal reflux disease. Beyond the gastrointestinal tract, H2R is expressed by multiple immune cells, yet little is known about the immunomodulatory effects of such treatment. Clinical reports have associated H2R blockade with leukopenia, neutropenia, and myelosuppression, and has been shown to provide clinical benefit in certain cancer settings. To systematically assess effects of H2R blockade on key immune parameters, a single-center, single-arm clinical study was conducted in 29 healthy subjects. Subjects received daily high dose ranitidine for 6 weeks. Peripheral blood immunophenotyping and mediator analysis were performed at baseline, 3 and 6 weeks into treatment, and 12 weeks after treatment cessation. Ranitidine was well-tolerated, and no drug related adverse events were observed. Ranitidine had no effect on number of neutrophils, basophils or eosinophils. However, ranitidine decreased numbers of B cells and IL-2Rα (CD25) expressing T cells that remained lower even after treatment cessation. Reduced serum levels of IL-2 were also observed and remained low after treatment. These observations highlight a previously unrecognised immunomodulatory sustained impact of H2R blockade. Therefore, the immune impacts of H2R blockade may require greater consideration in the context of vaccination and immunotherapy.

IL-15 is a cytokine playing a crucial role in the function of immune cells, including NK and CD8 T cells. In this study, we demonstrated that in vivo, in mice, IL-15–prestimulated NK cells were no longer able to respond to a second cycle of IL-15 stimulation. This was illustrated by defects in cell maturation, proliferation, and activation, seemingly linked to the environment surrounding NK cells but not related to the presence of CD4 regulatory T cells, TGF-β, or IL-10. Moreover, NK cells from immunodeficient mice could respond to two cycles of IL-15 stimulation, whereas an adoptive transfer of CD44+CD8+ cells impaired their responsiveness to the second cycle. Conversely, in immunocompetent mice, NK cell responsiveness to a second IL-15 stimulation was restored by the depletion of CD8+ cells. These biological findings refine our understanding of the complex mode of action of NK cells in vivo, and they should be taken into consideration for IL-15–based therapy.

Interleukin 2 and IL-15 are two closely related cytokines, displaying important functions in the immune system. They share the heterodimeric CD122/CD132 receptor to deliver their signals within target cells. Their specificity of action is conferred by their α receptor chains, IL-2Rα and IL-15Rα. By combining an increased affinity for CD122 and an impaired recruitment of CD132, we have generated an original molecule named IL-2Rβ/γ (CD122/CD132) inhibitor (BiG), targeting the CD122/CD132 receptor. BiG efficiently inhibited IL-15– and IL-2–dependent functions of primary cells, including CD8 T and NK cells, in vitro and in vivo. We also report a differential dynamic of action of these cytokines by highlighting a major role played by the IL-2Rα receptor. Interestingly, due to the presence of IL-2Rα, BiG had no impact on IL-2–dependent regulatory T cell proliferation. Thus, by acting as a fine switch in the immune system, BiG emphasizes the differential roles of these two cytokines.