Mature Cystic Fibrosis Airway Neutrophils Suppress T Cell Function: Evidence for a Role of Arginase 1 but Not Programmed Death-Ligand 1

Abstract

Bacteria colonize cystic fibrosis (CF) airways, and while T cells with appropriate antigen specificity are present in draining lymph nodes, they are conspicuously absent from the lumen. To account for this absence, we hypothesized that polymorphonuclear neutrophils (PMNs), recruited massively into the CF airway lumen and actively exocytosing primary granules, also suppress T-cell function therein. Programmed Death-Ligand 1 (PD-L1), which exerts T-cell suppression at a late step, was expressed bimodally on CF airway PMNs, delineating PD-L1hi and PD-L1lo subsets, while healthy control (HC) airway PMNs were uniformly PD-L1hi. Blood PMNs incubated in CF airway fluid lost PD-L1 over time, and in coculture, antibody blockade of PD-L1 failed to inhibit the suppression of T-cell proliferation by CF airway PMNs. In contrast with PD-L1, arginase 1 (Arg1), which exerts T-cell suppression at an early step, was uniformly high on CF and HC airway PMNs. However, arginase activity was high in CF airway fluid and minimal in HC airway fluid, consistent with the fact that Arg1 activation requires primary granule exocytosis, which occurs in CF, but not HC, airway PMNs. In addition, Arg1 expression on CF airway PMNs correlated negatively with lung function and positively with arginase activity in CF airway fluid. Finally, combined treatment with arginase inhibitor and arginine rescued the suppression of T-cell proliferation by CF airway fluid. Thus, Arg1 and PD-L1 are dynamically modulated upon PMN migration into human airways, and, Arg1, but not PD-L1, contributes to early PMN-driven T-cell suppression in CF, likely hampering resolution of infection and inflammation.

Neutrophils in cystic fibrosis

“…More recently, CF airway neutrophils, with full mature phenotype, were described to release arginase 1, activate it through proteolytic cleavage associated with primary granule exocytosis, which deprive the milieu in arginine and actively modulate T-cell function. This study supports an active inhibition of T-cell response due to neutrophil activity in CF airways (Ingersoll et al, 2015). Thus, as shown in Figure 1, the pathological events occurring in CF airways appear to trigger specific reprogramming of these cells, suggesting that neutrophils are not just passive shortlived and catabolic cells, but rather stay viable and actively contribute to airway disease (Tirouvanziam, 2006).…”

“…New neutrophil phenotypes, such as T-cell suppressive granulocytic myeloid-derived-suppressor cells (MDSCs) (Rieber et al, 2013;Ingersoll et al, 2015) broaden the repertoire of neutrophil versatility in CF and underscore their importance beyond direct pathogen killing. While the surrounding pro-inflammatory CF microenvironment substantially affects neutrophil phenotype and function, the intrinsic CFTR defect also seems to modulate neutrophil homeostasis and granule release (Pohl et al, 2014).…”

The Blood Transcriptome of Experimental Melioidosis Reflects Disease Severity and Shows Considerable Similarity with the Human Disease

“…Surprisingly a prominent finding revealed by our transcriptomic analysis of both infected mice and humans was the prominent up-regulation in both blood and tissue of Arginase-1, which led us to investigate and confirm its presence at the protein level within the lesions of infected mice. Arginase-1 is known to antagonise the iNOS microbicidal pathway and to inhibit T cell immunity in other infections (27) (28) (29) (30) and thus may be a contributing factor to why in B. pseudomallei infection sterilising immunity is rarely achieved.…”

Innate Immunity of the Lung: From Basic Mechanisms to Translational Medicine

“…Further studies revealed a role for airway neutrophils in regulation of the adaptive immune system, further emphasizing the multidimensional importance of neutrophil plasticity [37]. For example, a strong immunosuppressive function was identified in CF airway neutrophils, which can downregulate T-cell activity through the release and activation of arginase I, concomitant with granule exocytosis [49]. Activated neutrophils may also impact T cells positively within CF airways but also within the lymphatic compartment by displaying antigen-presenting cell capabilities (e.g., expression of CD80, CD86, and MHC II).…”