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The Journal of Immunology, 1999, 162: 5033-5036.
Copyright © 1999 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Protective Response to Pulmonary Injury Requires {gamma}{delta} T Lymphocytes1

Donald P. King2,*, Dallas M. Hyde{dagger}, Kenneth A. Jackson*, Denise M. Novosad{ddagger}, Terri N. Ellis{ddagger}, Lei Putney{dagger}, Mary Y. Stovall{dagger}, Laura S. Van Winkle{dagger}, Blaine L. Beaman{ddagger} and David A. Ferrick*

Departments of * Pathology, Microbiology, and Immunology, and {dagger} Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, CA 95616; and {ddagger} Department of Medical Microbiology, School of Medicine, University of California, Davis, CA 95616


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
{gamma}{delta} intraepithelial lymphocytes are thought to coordinate responses to pathogens that penetrate the epithelial barrier. To directly test this, mice were inoculated with Nocardia asteroides. At doses that were nonlethal for control mice, {gamma}{delta}-deficient mice became severely ill and died within 14 days. Histologic examination of these lungs demonstrated the presence of severe tissue damage and unimpeded bacterial growth in the {gamma}{delta}-deficient mice compared with neutrophilic lesions and clearance of the organism in control mice. Interestingly, ozone exposure that targets a comparable lung region also resulted in diffuse epithelial necrosis associated with a similar lack of neutrophil recruitment in {gamma}{delta}-deficient mice. These data demonstrate that {gamma}{delta} intraepithelial lymphocytes can protect the host from pathogenic and nonpathogenic insults by targeting the inflammatory response to epithelial necrosis.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The residency of {gamma}{delta} intraepithelial lymphocytes (IELs)3 within the epithelial borders (1, 2), along with their ability to respond to infection by producing cytokines (3, 4, 5, 6, 7, 8, 9, 10), has led investigators to speculate that this intimate association is crucial for the maintenance of epithelial homeostasis (2, 11, 12). In contrast to {alpha}ß T cells, the {gamma}{delta} TCR does not recognize MHC-bound processed peptides (13). The {gamma}{delta} TCR binds unprocessed Ags such as MHC class I-like molecules that have been shown to be up-regulated on stressed and injured cells (14). Furthermore, it is now appreciated that {gamma}{delta} T cells have additional attributes that are not associated with classical notions of acquired immune surveillance. Such T cells have been shown to secrete factors that can influence epithelial growth and repair (15) as well as those that can recruit inflammatory cells (16, 17), suggesting that this dual functionality defines a unique surveillance role for {gamma}{delta} IELs.

The pulmonary epithelium is the largest mucosal barrier that separates the host from its environment. Damage to the lung by the environment occurs at this epithelial border. Within this site, the balance between mechanisms that promote epithelial growth and repair vs inflammation to wall off and contain damage is critical for maintenance of the lung microenvironment.

The function of pulmonary {gamma}{delta} IELs was investigated using two independent experimental models that resulted in airway epithelial cell damage. Nocardia asteroides, a facultative intracellular Gram-positive bacterium, was employed to generate an infectious insult to the airway epithelium of {gamma}{delta}-deficient and control mice. These organisms rapidly penetrate and injure tracheobronchial epithelial cells and are cleared by a strong inflammatory host response involving the recruitment of neutrophils (18). N. asteroides targets the nonciliated epithelial cells of the bronchus and bronchioles (19). Likewise, a similar lung region was targeted for injury by a nonpathogenic insult, ozone. A short-term inhalation of ozone causes damage predominantly to ciliated epithelial cells in the anterior nasal cavity, trachea, and central acinus. This acute injury results in necrosis of ciliated cells, deciliation, and degranulation of secretory cells in conducting airways and necrosis of type I cells and ciliated cells in proximal acini. Maximum epithelial necrosis occurs in terminal bronchioles during the first 24 h after the initiation of exposure in the rat, and necrosis during this period is accompanied by a significant influx of neutrophils (20, 21). Using both agents to damage the same region of the lung epithelium allowed us to contrast the ability of {gamma}{delta} IELs to respond to injury in the presence or absence of foreign Ag. The purpose was to determine whether or not the response of {gamma}{delta} IELs to acute injury required pathogen-specific recognition.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice

Breeding pairs of TCR {gamma}{delta}-deficient (22) mice (knockout (KO): C57BL/6J-Tcrdtm1/Mom) were obtained from The Jackson Laboratory (Bar Harbor, ME) and were housed under specific pathogen-free conditions. Age-matched KO and heterozygous control (+/-) mice were bred for experiments using homozygous KO and +/- parents. The phenotype of these progeny was established by two-color flow cytometric analysis using CD3 (145-2C11) and {gamma}{delta}-specific (GL-3) mAbs (PharMingen, San Diego, CA) and was subsequently confirmed by PCR analysis of DNA extracted from tails. The experimental protocols used in this study were approved by the University of California Davis Animal Care and Use Committee.

Nocardia infection

N. asteroides (GUH2 strain) were grown to mid-log phase for 16 h from laboratory stocks in brain heart infusion media. A single-cell suspension was prepared by slow speed-differential centrifugation as described previously and resuspended in brain heart infusion (23). Female mice (8–12 wk of age) weighing 15–20 g were anesthetized by an i.p. injection of 50 mg/kg Nembutal (Abbott Laboratories, Chicago, IL). A total of 50 µl of the prepared inoculum was administered by i.n. aspiration to the mice. At 3 h postinoculation, the left lobes of the lungs of five mice were harvested, homogenized, and plated-out to determine actual dose of bacteria that the animals received.

Ozone exposure

Mice were exposed in exposure chambers of 4.2 m3 capacity that were ventilated at a rate of 30 changes per hour with chemical, biologic, and radiologic filtered air at 24 ± 2°C and 40–50% relative humidity. Oxygen was passed through a Sanders Model 25 Ozonizer (Eltze, Germany) to produce ozone. Ozone concentrations were measured using a UV ozone monitor (model 1003-AH; Dasibi Environmental, Glendale, CA) and reported with respect to the UV photometric standard. Filtered air and ozone mice were exposed to 0.0 and 1.5 parts per million of ozone for 8 h, followed by postexposure in filtered air for 8 h. Following 8 h postexposure in filtered air, mice were killed using sodium pentobarbital overdose. The lung was lavaged with PBS, and the recovery was 89 ± 6% of the volume infused for all mice with no significant differences per groups. The total nucleated cell count was estimated using a Coulter counter (Coulter, Miami, FL), and a differential count on a minimum of 300 cells was completed using a cytospin (Shandon, Pittsburgh, PA) and Diff-Quik (Dade Diagnostics, Puerto Rico) stain. Values were expressed as total cells recovered from lavage of the lung.

Histology

For histopathology, lungs were fixed with 10% zinc-formalin (Anatech, Battle Creek, MI) by infusion through a tracheal cannula at 30 cm of H2O pressure for a minimum of 1 h. Tissue blocks were sampled in a systematic uniform manner from the lung lobes, dehydrated in a graded series of ethanols, and embedded in paraffin for light microscopy according to standard procedures. Several 5-µm sections were cut from the embedded tissue. The tissues were stained with hematoxylin-eosin or with Brown and Brenn Gram stain and evaluated by light microscopy.

Estimation of cellular composition of lesions

The volume density of lesion with the lung, VLES,L, was determined by point-counting techniques using the formula VLES,L = PLES/PL, where PLES is the number of points hitting a lesion divided by PL, the total number of points hitting lung tissue. Because of the patchy distribution of the lesion, each section was scanned in a systematic uniform manner at a final magnification of x10 with a 42-point lattice test system until all fields (20–25 fields) in the section had been evaluated. A mean volume density of lesion was obtained by averaging the VLES,L values contributed by each lung. Using periodic area weighted sampling, the volume density of the components of the lesion (polymorphonuclear leukocytes (PMNs), debris, cell matrix, and mononuclear cells) were determined by point-counting techniques at x40 magnification.

Statistics

Differences between groups were analyzed using ANOVA and Fisher’s least significant difference test (Systat 8.0; SPSS Inc., Chicago, IL). All data are presented as means ± SEM. Statistical significance is accepted for p < 0.01.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
A striking difference was observed in the mortality of {gamma}{delta}-deficient mice compared with control mice after i.n. inoculation with N. asteroides (Fig. 1Go). Infected {gamma}{delta}-deficient mice (n = 13) became overtly ill, displayed labored breathing, and died within 14 days. In contrast, control mice (n = 15) displayed no overt clinical symptoms, and all mice successfully cleared the infective organism within 7 days. To investigate the underlying cellular mechanisms responsible for this difference in mortality, lungs were collected from mice 48 h postinfection. Histologic examination of the lung parenchyma from infected {gamma}{delta}-deficient mice revealed the presence of multifocal areas of acute necrosis with a notable lack of inflammatory cells (Figs. 2GoB and 3). We also observed frequent small lesions within the conducting airways of these mice (data not shown). All lesions had an abundance of Gram-positive N. asteroides in them, and these findings were consistent with unimpeded and disseminated bacterial growth in the {gamma}{delta}-deficient mice (Fig. 2GoD). In contrast, lungs from infected control mice primarily contained multifocal parenchymal lesions with an abundance of inflammatory cells that were predominately neutrophils (Figs. 2GoA and 3). These recruited cells ultimately led to clearance of the pathogen (Fig. 2GoC) and survival of the mice.



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  		FIGURE 1. Survival curves of N. asteroides-infected control (n = 15) and {gamma}{delta}-deficient (n = 13) mice. Mice were infected i.n. with 9.5 x 106 N. asteroides organisms; subsequent survival was monitored daily.

 


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  		FIGURE 2. A, Representative light micrograph of lung tissue from control mice showing an abundance of inflammatory cells and neutrophils in parenchymal lesions and a central airway location (arrow). Bar = 50 µm. B, Representative light micrograph of a parenchymal lesion with a notable lack of inflammatory cells and acute necrosis in a central location in KO mice. Bar = 50 µm. C, Higher magnification view of a serial section of A above shows a few phagocytosed N. asteroides organisms identified by Gram stain (arrows) in control mice. Bar = 10 µm. D, Higher magnification view of a serial section of B above shows an abundance of filamentous N. asteroides organisms detected by Gram staining in KO mice. Bar = 10 µm. E, Representative light micrograph showing repaired terminal bronchiolar (TB) epithelium following ozone exposure of a control mouse. Bar = 10 µm. F, Representative light micrograph showing lack of repair in terminal bronchiolar epithelium (TB) following ozone exposure in a KO mouse. Note the presence of alveolar macrophages adjacent to exposed basal lamina (arrows) and cellular debris in the bronchiolar lumen. Bar = 10 µm.

 
To assess the response of {gamma}{delta} IELs to epithelial damage mediated by a nonpathogenic insult, both {gamma}{delta}-deficient and control mice were exposed to ozone. Although the control mice were able to mount an effective acute inflammatory response rich in neutrophils to isolate and clear damaged epithelium, {gamma}{delta}-deficient mice were unable to effectively recruit inflammatory cells, as observed in the N. asteroides challenges (Fig. 4Go). This resulted in a decreased clearance of necrotic epithelial cells in terminal airways that was characterized by either accumulations of necrotic epithelial cells in lavage fluid or the presence of bare basal lamina marking the absence of epithelial repair shown in histology (Fig. 2GoF). These lesions are very similar to those observed with ozone exposure in neutrophil-depleted rats (24). These data suggest that in the acute phases of infectious epithelial injury, {gamma}{delta} IELs recognize and respond to self-tissue damage.



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  		FIGURE 4. Total cells obtained by bronchoalveolar lavage (in thousands) showed no difference between ozone-exposed control mice (Ctrl) (n = 8) and KO mice (n = 10). There were significantly (*, p < 0.01) elevated numbers of PMNs and macrophages (MAC) in control mice in comparison with significant (*, p < 0.01) increases of epithelial cells (EPI) in KO mice. Lymphocytes (LYMPH) were not significantly different between the two groups.

 
Although {gamma}{delta} T cells have been shown to contribute to the overall protection of the host against a variety of pathogenic insults (25, 26, 27, 28, 29, 30, 31, 32), they have not been generally considered to be absolutely required for survival. Many theories have placed them at the initial phases of the immune response as a recruiter of inflammatory cells and regulator of inflammation (2, 9, 10, 16, 33). Recently, {gamma}{delta} IELs have been also implicated in epithelial repair because of their unique ability to produce growth factors such as keratinocyte growth factor (15) and epidermal growth factor (D.A.F., unpublished observation). Our data clearly demonstrate an essential role for {gamma}{delta} IELs in the survival of the host against a lung infection with an epithelial-invasive culture of N. asteroides. This protection seems to depend upon an intimate link between epithelial damage and {gamma}{delta} IEL responsiveness that is manifested by recruitment and perhaps also activation of inflammatory cells.

The acuteness of the Nocardia infections and the lack of foreign Ag in the ozone exposures imply that {gamma}{delta} IELs are able to recruit inflammatory cells by responding to epithelial damage alone. Although it has been clearly demonstrated that {gamma}{delta} TCRs do not recognize processed peptide Ags complexed to self-MHC molecules (13), there is evidence to show that they can recognize highly conserved nonprotein Ags (34, 35) and, perhaps more relevant to this study, stress-induced MHC class I-like molecules (14). Therefore, invasion of epithelium may lead to the up-regulation of self-associated stress molecules that are recognized by {gamma}{delta} IELs.

The notion that {gamma}{delta} T cells are able to recognize injury regardless of whether or not the cell is infected distinguishes them significantly from {alpha}ß T cells. The location of {gamma}{delta} IELs at the mucosal interface and their ability to produce factors that influence repair, inflammation, and acquired immunity makes them ideal candidates to monitor epithelial integrity. Within these epithelial borders, they may function as a rheostat for immune responsiveness by monitoring epithelial cell damage. Further investigations into their ability to promote protective immunity as well as epithelial repair are ongoing.



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  		FIGURE 3. The volume of lesion expressed as percent lung volume showed no difference between control mice (Ctrl) (n = 5) and KO mice (n = 5). Of the volume components of the lesion (PMNs, debris, cell matrix, and mononuclear cells), PMNs were significantly increased (*, p < 0.01) in control mice and cellular debris was significantly increased (*, p < 0.01) in KO mice compared with the other group.

 

   Acknowledgments
 
We thank Brian Tarkington and Eugenio Ocampo for technical assistance, Julie Schwartz for histologic interpretation, and Nancy Tyler for help with manuscript preparation.


   Footnotes
 
1 This work was supported by Grant GM46412-07 from the National Institutes of Health, Grant R01-HL59821 from the National Heart, Lung, and Blood Institute, and Grant ES-00628 from the National Institute on Environmental Health Sciences. Back

2 Address correspondence and reprint requests to Dr Donald P. King, Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, CA 95616. E-mail address: Back

3 Abbreviations used in this paper: IEL, intraepithelial lymphocyte; KO, knockout; i.n., intranasal(ly); PMN, polymorphonuclear leukocyte. Back

Received for publication January 20, 1999. Accepted for publication February 25, 1999.


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B.B. Moore, T.A. Moore, and G.B. Toews
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F. M. Spada, E. P. Grant, P. J. Peters, M. Sugita, A. Melian, D. S. Leslie, H. K. Lee, E. van Donselaar, D. A. Hanson, A. M. Krensky, et al.
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