Abstract
γδ T cells commonly associate with mucosal and epithelial sites, fulfilling a variety of immunoregulatory functions. While lung γδ T cells have well-characterized pro-inflammatory activity, their potential role in the resolution of lung inflammation has yet to be explored in any detail. Indeed, given the importance of minimizing inflammation, the cellular mechanisms driving the resolution of lung inflammation are poorly understood. Using a murine model of acute Streptococcus pneumoniae-mediated lung inflammation, we now show that resolution of inflammation following bacterial clearance is associated with a > 30-fold increase in γδ T-cell number. Although inflammation eventually resolves in TCRδ−/− mice, elevated numbers of alveolar macrophages and pulmonary dendritic cells, and the appearance of well-formed granulomas in lungs of TCRδ−/− mice, together indicated a role for γδ T cells in regulating mononuclear phagocyte number. Ex vivo, both alveolar macrophages and pulmonary dendritic cells were susceptible to lung γδ T cell-mediated cytotoxicity, the first demonstration of such activity against a dendritic cell population. These findings support a model whereby expansion of γδ T cells helps restore mononuclear phagocyte numbers to homeostatic levels, protecting the lung from the consequences of inappropriate inflammation. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Highlights
Appropriate regulation and resolution of acute pulmonary inflammatory responses are critical for maintenance of tissue integrity, avoidance of host-mediated pathology, and host survival
Since activated splenic and peritoneal macrophages are susceptible to TCRδ-dependent, γ δ T-cell-mediated killing [10,11,12], we examined whether γ δ T cells might exert cytotoxic activity against alveolar macrophage (AM) and pulmonary dendritic cell (pulDC) following pneumococcal challenge
The present study uses a model of pneumococcal challenge to examine possible mechanisms underlying the resolution of inflammation following pathogen clearance
Summary
Appropriate regulation and resolution of acute pulmonary inflammatory responses are critical for maintenance of tissue integrity, avoidance of host-mediated pathology, and host survival. AMs control the threshold at which innate responses to streptococcal infection are initiated [4] and are involved in resolution of acute pulmonary inflammation through phagocytic clearance of apoptotic neutrophils [5,6,7]. We have previously described a model of S. pneumoniae-induced lung inflammation in which an acute, phagocyte-dominated inflammatory response results in pathogen clearance within 5 days [2]. We demonstrate that the resolution phase of S. pneumoniae-induced pulmonary inflammation is accompanied by a more than 30-fold increase in lung γ δ T-cell number These cells do not contribute to bacterial clearance, but are directly cytotoxic against AMs and pulDCs. Together with the appearance of small coherent granulomas in TCRδ−/− mice, these studies suggest that cytotoxic γ δ T cells play an important role in regulating the expansion and homeostatic control of these inflammatory cell populations
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