Why do some patients seem to accumulate large numbers of medical problems while others stay essentially healthy? Is it genetics, is it what they eat, or does one problem directly trigger the next? In particular, why do patients with chronic inflammatory conditions seem to be at higher risk for cancer and for poor prognoses after cancer diagnosis? Does the inflammatory process promote cancer through increased oxidative damage or direct suppression of anti-tumor immune responses?
In this paper, Munder et al. show that activated human neutrophils directly suppress the ability of T cells to be activated through the T-cell receptor. This brake occurs because of a sudden depletion of the local T-cell milieu of the amino acid arginine, which is caused by the local release of arginase from neutrophil granules. Not only is overall T-cell metabolism and cell proliferation repressed, but the ζ chain of CD3 is specifically downregulated, so that no T-cell activation signals are delivered from the cell surface after antigen binding. So in a locally inflamed environment, T cells are essentially paralyzed. One could easily imagine that local or chronic generalized inflammation would lead to depressed T-cell responses, including both response to infectious pathogens and tumor antigens.
In Brief
This link to arginase secretion had been previously detected in the mouse, but many mouse cells secrete arginase, including macrophages and dendritic cells1 . Not so in humans, where arginase production is strictly limited to neutrophils. Munder and colleagues demonstrate every step of the arginase-T-cell paralysis link in human neutrophils. In addition, by showing that neutrophils from a patient with congenital arginase deficiency do not suppress T cells, they show that arginase is specifically required for this T-cell paralysis. This is important, because it suggests that specific pharmacologic inhibitors of arginase activity could be developed to specifically disrupt inflammation-induced T-cell anergy. For now, it suggests yet another reason why aspirin and anti-inflammatory homeopathic interventions might be of real benefit to our patients. And of course, this reinforces the lesson that basic scientists would be well served to closely consider folk wisdom for possible unsuspected physiology, if we are to truly uncover nature’s mysteries.
References
Competing Interests
Dr. Emerson indicated no relevant conflicts of interest.
