Natural Killer Cell Phenotypic Changes and Activating Receptor Loss Posttrauma
Nagham Bazzi, Linda Stempora, Hannah Hensman, Patricia Martinez Quinones, Isabel Rodriguez Negron, Kateryna Krynychka, Rondi B. Gelbard, Scott F. Grey, Seth A. Schobel, Eric Elster, Joseph Fernandez-Moure, Allan D. KirkBackground:
Trauma induces significant physiological changes that can lead to substantial morbidity and mortality. Many of these changes alter immune homeostasis, which underlies seemingly disparate syndromes of systemic inflammation and global immune suppression, the causes of which remain unclear. Innate immune cells play a key role in the response to trauma, and recent studies have suggested that natural killer (NK) cells are dynamically responsive to mild versus severe systemic trauma.
Materials and Methods:
Herein, we examined NK cell phenotypic maturation in trauma (n = 137) and nontrauma (n = 45) patients. Peripheral blood samples were collected from adult patients within 24 hours of injury and interrogated by flow cytometry for surface markers of maturation (CD16, CD56, and CD57) and associated activating (NKP30, NKP46, and NKG2D) and inhibiting (KIR2DL1 and KIR2DL2) receptors.
Results:
Following trauma, peripheral NK cells were phenotypically less cytokine-dominant (CD56 bright ), more mature, and cytotoxic (CD56 dim , CD16 + ). However, in severely injured patients, these changes were not accompanied by an expected increase in the expression of activating receptors, particularly those sensing danger motifs displayed on injured and stressed cells. Indeed, cytotoxic NK cells lacking NKP30, NKP46, and NKG2D were significantly more prevalent in severely injured patients.
Conclusions:
This pattern suggests a widespread functional shift in NK cells activated by severe trauma away from the expression of receptors involved in recognizing stressed or “damaged self” cells. The absence of activating receptors could be acutely adaptive, avoiding broad cytotoxic responses in the face of overwhelming cell injury, but problematic several days after trauma when infectious complications arise. These data suggest one of many mechanistic explanations for the immune dysregulation seen in individuals who survive major trauma.