Local Microenvironment Controls the Compartmentalization of NK Cell Responses during Systemic Inflammation in Mice

Abstract

Systemic inflammatory response syndrome is a whole-body reaction to a triggering insult that often results in life-threatening illness. Contributing to the development of this inflammatory cascade are numerous cellular partners, among which NK cells were shown to play a key role. Accumulating evidence points to organ-specific properties of systemic inflammation and NK cells. However, little is known about compartment-specific activation of NK cells during systemic inflammatory response syndrome or the relative contribution of NK cell-intrinsic properties and microenvironmental cues. In this study, we undertook a sequential characterization of NK responses in the spleen, lungs, bone marrow, peritoneum, and blood using a mouse model of endotoxemia. We report that, despite similar systemic dynamics of NK cell responses, expression of activation markers (CD69 and CD25) and effector molecules (IFN-γ, granzyme B, and IL-10) display organ-specific thresholds of maximum activation. Using adoptive transfers of spleen and lung NK cells, we found that these cells have the capacity to quickly adapt to a new environment and adjust their response levels to that of resident NK cells. This functional adaptation occurs without significant alterations in phenotype and independently of subpopulation-specific trafficking. Thus, using a dynamic in vivo-transfer system, to our knowledge our study is the first to report the compartmentalization of NK cells responses during systemic inflammation and to show that NK cell-intrinsic properties and microenvironmental cues are involved in this process, in a sequential manner.

The biology of natural killer cells during sepsis

“…found that, in the setting of sepsis, it is the local microenvironment that mediated the functional adaptation of tissue‐resident NK cells. In this study, tissue‐resident NK cells displayed organ‐specific thresholds of maximum activation and effector functions in lung, spleen, peritoneum, bone marrow and blood . In another study, Victorino et al .…”

“…In this study, tissue-resident NK cells displayed organ-specific thresholds of maximum activation and effector functions in lung, spleen, peritoneum, bone marrow and blood. 98 In another study, Victorino et al 99 showed that NK cells resident in kidney directly mediated ischaemic kidney injury, which is common during septic shock and an indicator of poor prognosis. It is therefore noteworthy to perform more studies to examine how tissueresident NK cells could modulate compartment-specific inflammation and the multiple organ dysfunctions in lethal sepsis.…”

Stereotactic Ablative Radiation Therapy Induces Systemic Differences in Peripheral Blood Immunophenotype Dependent on Irradiated Site

“…33,34,35 As natural killer (NK) cells comprise a large portion of the immunotolerant organs such as the lung and liver, we hypothesized that radiation to these sites may cause unique changes in specific NK cell populations. 33,36 We hypothesized that the systemic immune response to SAR would differ based on irradiated site, and set out to gain a comprehensive understanding of these differences to refine future clinical trials combining radiotherapy and immunotherapy. We prospectively collected blood samples prior to SAR and 1–2 weeks post-SAR from patients undergoing SAR to lung, liver, bone, or brain to measure changes in markers of the systemic immune response, such as cytokine/chemokine signatures and immunophenotype changes in peripheral blood mononucleated cells (PBMCs).…”

H3K4me1 Supports Memory-like NK Cells Induced by Systemic Inflammation

“…Mice exhibited transient weight loss, clinical signs of inflammation, and limited mortality. Using this model, we had previously shown that NK cells are systemically activated over a 48 h acute period (Rasid et al, 2016). In the present study, we focused on the impact of endotoxemia on NK cells 14 days after LPS injection.…”