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First published online on July 23, 2007
Chest, doi:10.1378/chest.07-0128
doi:10.1378/chest.07-0128
(Chest. 2007; 132:1291-1297)
© 2007 American College of Chest Physicians
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Expansion of Pulmonary CD8+CD56+ Natural Killer T-Cells in Hypersensitivity Pneumonitis*

Peter Korosec, PhD; Katarina Osolnik, MD; Izidor Kern, MD; Mira Silar, BSc; Katja Mohorcic, MD and Mitja Kosnik, PhD, MD

* From the University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.

Correspondence to: Peter Korosec, PhD, Laboratory of Immunology and Molecular Biology, University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia; e-mail: peter.korosec{at}klinika-golnik.si

Abstract

Background: Natural killer T (NKT) cells, a newly identified subgroup of T cells with immunoregulatory function, may be implicated in the pathogenesis of interstitial lung disease (ILD).

Methods: We used multiparameter flow cytometry with antibodies to CD3, CD4, CD8, CD14, CD19, CD45, CD16/56, CD56, CD161, and V{alpha}24 invariant T-cell receptor (TCR) in BAL fluid (BALF) to examine the frequency and distribution of pulmonary NKT cells in several cases of ILD. We included 57 patients with sarcoidosis and 17 patients with hypersensitivity pneumonitis.

Results: We found significantly higher frequencies of pulmonary NKT cells in patients with hypersensitivity pneumonitis in comparison to the other study patients with ILD (median proportion of NKT cells, 11%; range, 3 to 38%; vs 3%; range, 0 to 16%; p < 0.0001). In contrast, there was no difference in the proportion of conventional natural killer cells. We found that a major subset of NKT cells in the BALF of patients with hypersensitivity pneumonitis was a CD8+CD56+ population that did not express the invariant TCR.

Conclusions: These results suggest the involvement of NKT cells in the pathogenesis of hypersensitivity pneumonitis.

Key Words: interstitial lung diseases • hypersensitivity pneumonitis • natural killer T cells

Natural killer T (NKT) cells comprise a unique subgroup of lymphocytes that express features of both T and natural killer (NK) cells and coexpress T cell receptors (TCRs) as well as markers associated with NK cells such as CD56 and/or CD161.1 In humans, two major subsets of NKT cells have been described.2 The more widely studied subset are CD1d-dependent cells (called V{alpha}24 invariant NKT cells), which express a highly restricted TCR with an invariant V{alpha}24-J{alpha}18 chain (preferentially paired with Vß11) and are dependent on the presentation of the glycolipid antigen through CD1d, a member of class I nonpolymorphic antigen-presenting molecules.3 The second class of NKT cells, CD1d-independent cells, express nonbiased TCR-{alpha}ß repertoire and are independent of CD1d for their activity.456 On activation, NKT cells rapidly produce both T-helper type 1 (Th1)- and T-helper type 2-specific cytokines and exhibit both antigen specific and NK-like cytolytic activities.26 This rapid cytokine production is a manifestation of innate-like immunity and provides NKT cells with the ability to link the innate and adaptive immune responses. The role of NKT cells in humans is not completely understood, and it has mainly been connected with priming and regulating the immune responses in cancer, autoimmunity, and infectious diseases.678 However, it has been shown that NKT cells might play a very prominent pathogenic role in two common lung diseases: asthma and sarcoidosis. Akbari et al9 demonstrated an increased number of invariant NKT cells in the lungs of patients with asthma and a requirement for invariant NKT cells was indicated in the development of allergen-induced airway hyperreactivity in mice.101112 More recently, these findings have been challenged by Vijayanand et al,13 who reported significantly lower invariant NKT cells counts then those found by Akbari et al.9 Ho et al14 suggested that loss of immunoregulation by invariant NKT cells could explain the amplified and prolonged T-cell activity characterizing sarcoidosis. However, limited data detailing the role of NKT cells in other immunologically mediated lung diseases exist, especially those characterized by heavy lung T-cell accumulation. As a result, we studied the frequency and distribution of NKT cells in BAL fluid (BALF) from patients with different types of interstitial lung diseases (ILDs), ranging from sarcoidosis to hypersensitivity pneumonitis.

Materials and Methods

Patients
Patients (n = 74) were recruited from the University Clinic of Respiratory and Allergic Diseases over a 1.5-year period. All patients were subjected to a diagnostic workup, which included posteroanterior chest radiography, high-resolution CT, pulmonary function tests (Table 1 ), and fiberoptic bronchoscopy with biopsy and BAL.


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  		Table 1.. BALF Cell Counts and Results of Lung Function Testing From Study Patients With Sarcoidosis and Hypersensitivity Pneumonitis*

 
The diagnosis of ILD was in agreement with the statement adopted by the joint committees of American Thoracic Society and European Respiratory Society.151617 We enrolled 57 patients with pulmonary sarcoidosis (14 patients with Löfgren syndrome [mean age, 46 years; range 25 to 74 years]; 32 women; 4 smokers; and 8 ex-smokers) and 17 patients with hypersensitivity pneumonitis (mean age, 63 years; range, 22 to 77 years; 6 women; 5 ex-smokers [4 were in the acute phase, 8 were in the subacute phase, and 5 were in the chronic phase at the time of sampling]). All patients gave written consent, and the study was approved by the National Ethics Committee (No. 68/03/20).

BAL Procedure
BAL was performed as previously described.18 Cytospins were stained according to the May-Grünwald Giemsa and Papanicolaou method. Differential cell counts were performed by one observer blinded to the clinical characteristics, counting 200 cells (Table 1).

Flow Cytometry
To identify lymphocyte subsets in BALF, flow cytometry was performed (FACSCalibur; BD Biosciences; San Jose, CA) using monoclonal antibody against CD3, CD4, CD8, CD14, CD19, CD45, and CD16/56 (all from BD Biosciences); CD56 (IQ Products; Groningen, The Netherlands); CD161 (Dako; Glostrup, Denmark); V{alpha}24 TCR (Immunotech; Marseille, France); and isotype-matched antibody controls (BD Biosciences) that were directly conjugated to either fluorescein isothiocyanate, phycoerythrin, or peridinin chlorophyll protein. Briefly, BALF was strained through a 70-µm cell strainer (BD Biosciences), cells were centrifuged at 460g for 5 min, resuspended in Hemaccel (Behringwerke; Marburg, Germany), and incubated with the respective monoclonal antibodies for 15 min, and then lysed, washed, and fixed. Labeled cells were analyzed by CellQuest software (BD Biosciences). Lymphocytes were distinguished on the basis of forward/side scatters and CD45 staining. NKT cells (CD3+CD16/56+), NK cells (CD3-CD16/56+), helper and suppressor T cells, and B lymphocytes were scored in percentages of lymphocytes. In patients with hypersensitivity pneumonitis, we further assessed the CD4+ and CD8+ NKT cells for the expression of CD56, CD161, and V{alpha}24 invariant TCR.

Statistical Analysis
The distribution of data were recalculated by the Shapiro-Wilk test. Since the data were not normally distributed, we performed a Mann-Whitney or Kruskal-Wallis test. The strength of association between NKT cells and other variables was obtained by the Spearman rank-order method. Probability values < 0.05 were accepted as significant. Analyses were performed using statistical software (SPSS, version 10.0; SPSS; Chicago, IL; and GraphPad Prism, version 4.0; GraphPad Software; San Diego, CA).

Results

When specimens of BALF obtained from all study patients were examined for the presence of CD4+ and CD8+ T cells, we observed a higher number of CD4+ cells with an increase in the CD4:CD8 ratio in patents with sarcoidosis and a lower number of CD4+ cells with a decreased or normal CD4:CD8 ratio in patients with hypersensitivity pneumonitis (Table 2 ).


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  		Table 2.. T Lymphocytes (CD3+CD4+ and CD3+CD8+) and B Lymphocytes (CD3-CD19+) in BALF From Study Patients*

 
In all study patients, the majority of pulmonary lymphocytes were T cells with a very low number of B lymphocytes (Table 2). We then examined the BALF for the presence of NKT cells and NK cells as detected by staining with monoclonal antibodies to CD3 and CD16/56. Surprisingly, we found that a much larger fraction of pulmonary lymphocytes coexpressing TCR and NK cell markers in patients with hypersensitivity pneumonitis than in the other study patients (Figs 1, 2 ). The median percentage of lymphocyte staining for CD3 and CD16/56 was 11% (range, 3 to 38%) for patients with hypersensitivity pneumonitis. This was significantly higher than in patients with sarcoidosis (3%; range, 0 to 16%; p < 0.0001, Mann-Whitney test). In contrast, no difference was detected in the frequency of pulmonary NK cells (CD3-CD16/56+) in our study patients (Fig 2; p = 0.74, Mann-Whitney test).


Figure 1
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  		Figure 1.. Flow cytometric analysis of NKT (CD+CD16/56+) and NK cells (CD3-CD16/56+) in BALF from three patients with sarcoidosis (top panels, A) and three patients with hypersensitivity pneumonitis (bottom panels, B). Cells were stained with monoclonal antibody against CD3 and CD16/56. Dot plots were generated after forward/side scatter lymphocyte gating.

 

Figure 2
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  		Figure 2.. Summary plot of an overall comparison of NKT (CD3+CD16/56+; p < 0.0001, Mann-Whitney test) and NK (CD3–CD16/56+; p = 0.74, Mann-Whitney test) cell frequencies in BALF between study groups of patients with ILDs. Horizontal solid bars indicate the median value for each group.

 
We also analyzed the frequencies of NKT cells in different clinical categories of our patients classified according to the mode of presentation (Löfgren syndrome vs other forms in the sarcoidosis group, and acute vs subacute vs chronic phases in patients with hypersensitivity pneumonitis). The frequency of CD3+CD16/56+ cells tend to be higher in Löfgren syndrome than in other forms of sarcoidosis (median, 4%; range, 1 to 15%; vs 2%; range, 0 to 16%), although the difference did not reach statistical significance (p = 0.09, Mann-Whitney test). There was no difference in the frequencies of NKT cells between patients with hypersensitivity pneumonitis in the acute, subacute, and chronic phases of disease (p = 0.62, Kruskal-Wallis test).

In patients with hypersensitivity pneumonitis, we performed a detailed phenotypic analysis of BALF NKT cells to determine the identity of those lymphocytes (Fig 3 ). We found that approximately 70 to 80% of NKT cells were CD8+CD56+ NKT cells and < 20% were CD4+CD56+ NKT cells (Figs 3, 4 ). In addition to the expression of CD56, the expression of CD161 has generally been regarded as an NKT cell-specific marker. However, the percentage of T lymphocytes coexpressing CD161 in patients with hypersensitivity pneumonitis was much lower and ranged from 0.7 to 11% (median, 3.7%) [Fig 3]. The expression of V{alpha}24 TCR was also tested. In patients with hypersensitivity pneumonitis, 0.34 to 3.4% (median, 1.1%) of pulmonary lymphocytes expressed the invariant V{alpha}24 TCR (Fig 4). We found that approximately 50% of those invariant NKT cells were CD4+ cells and approximately 40% of invariant NKT cells were CD8+ cells (approximately 10% of invariant NKT cells were negative for CD4 and CD8) [Fig 4].


Figure 3
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  		Figure 3.. Flow cytometric analysis of CD4+ and CD8+ cells for expression of CD56 (top panels), CD161 (center panels), and V{alpha}24 (bottom panels). Specimens were stained with monoclonal antibody against CD3, CD4, CD8, CD56, CD167, and TCR V{alpha}24. Dot plots were generated after forward/side scatter lymphocyte gating.

 

Figure 4
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  		Figure 4.. The percentage of NKT cells in BALF from the patient group with hypersensitivity pneumonitis expressing CD4, CD8, or neither. The bars in panel A (top) represent the percentage of CD56+ NKT cells. The bars in panel B (bottom) represent the percentage of V{alpha}24 invariant NKT cells that are CD4+, CD8+, or CD4–CD8– in each patient. ND = not defined.

 
Because a major fraction of pulmonary NKT cells in patients with hypersensitivity pneumonitis were CD8+, we wanted to establish whether there was any correlation between frequencies of NKT cells and predominance of CD8+ T cells. Nevertheless, there was no significant correlation between the frequencies of CD4 and CD8 T lymphocytes, other BALF cells, and the number of NKT cells (p > 0.15, Spearman method). Similar nonsignificant results were also observed in patients with sarcoidosis.

Discussion

Our study was the first to evaluate the quantitation and phenotypic analysis of NKT cells in BALF of patients with hypersensitivity pneumonitis. The results showed significantly higher NKT cell frequencies in BALF of the patients with hypersensitivity pneumonitis in comparison to other study cases of ILD. It is surprising that an increased number of NKT cells, but not the number of NK cells, was present in BALF of the patients with hypersensitivity pneumonitis, at the same time as previous studies19202122 demonstrated the increased number of NK cells. Nevertheless, we also show that increased number of lymphocytes in BALF of patients with hypersensitivity pneumonitis expressed NK cell markers. However, we further demonstrated that a great proportion of those cells expressed TCRs and thus are NKT cells rather than conventional NK cells. We believe this discrepancy may result from the fact that the previous authors192022 were limited by single antibody staining of lymphocyte surface markers using the peroxidase/antiperoxidase method23 and thus could not assess the coexpression of other surface antigens. In contrast, we used flow cytometry, which allowed for multiparameter analyses and enabled us to study different lymphocyte subgroups including NKT cells.24

We demonstrated that a great proportion of NKT cells in the BALF of patients with hypersensitivity pneumonitis were CD8+CD56+ subset of NKT cells, and the majority of those cells did not express the invariant V{alpha}24 TCR and CD161. Wajchman et al6 showed that this distinct CD8+CD56+CD161– NKT cell phenotype displays both antigen-specific (cytolytic T lymphocyte-like) as well as NK-like cytolytic activities that are independent of human leukocyte antigen class I and CD1 molecules. Pittet et al25 demonstrated that the potent cytolytic effector function of those cells closely correlates with CD56 surface expression and that those cells contain high amounts of intracellular perforin and granzyme B.

The increased number of CD8+CD56+ NKT cells in BALF of patients with hypersensitivity pneumonitis is interesting from several points of view. First, animal models suggested that the hypersensitivity pneumonitis is characterized by Th1 response26 and that interferon (IFN)-{gamma} is necessary for the development of disease, as IFN-{gamma} knockout mice are resistant to development of hypersensitivity pneumonitis.27 The exposure to interleulin-12 further enhanced IFN-{gamma} production and consequently modulated the severity of experimental hypersensitivity pneumonitis.28 Yamasaki et al29 demonstrated that clinical hypersensitivity pneumonitis is also characterized by Th1 response and the predominance of IFN-{gamma}–producing T-cells. Therefore, the possible importance of NKT cells in hypersensitivity pneumonitis is strengthened by the findings that CD8+CD56+ NKT cells are more potent inducers of Th1-mediated immune response relative to CD8+ T cells and that the interleukin-12– stimulated CD8+CD56+ cells can produce much larger amounts of IFN-{gamma} than CD8+ T cells.30 Second, the CD8+CD56+ NKT cells have also a unique chemokine receptor repertoire and a functional migratory response to the CCR5 ligand macrophage inflammatory protein ß.5 Macrophage inflammatory protein ß can markedly affect the mononuclear infiltration of the lung and was specifically detected in the BALF of patients with hypersensitivity pneumonitis in comparison to patients with sarcoidosis and cryptogenic fibrosing alveolitis.31

We found that in patients with hypersensitivity pneumonitis, only a small number of NKT cells were positive for staining with invariant V{alpha}24 antibody. Similar frequencies of invariant NKT cells (approximately 1% of lymphocytes) were also observed in BALF of healthy control subjects,913 and thus V{alpha}24-invariant NKT cells are unlikely to play an important role in the pathogenesis of hypersensitivity pneumonitis. Despite initial identification of NKT cells by invariant TCR {alpha} chain and NK surface antigens,1 CD56 and/or CD161, it is now evident that NKT cells comprise a heterogeneous subgroup with functionally distinct subpopulations that express different patterns of {alpha}/ß TCRs and NK cell antigens.23456

In general, there are low frequencies of NKT cells in the airway of patients with sarcoidosis.9133233 Ho et al14 suggested that low frequencies of invariant NKT cells demonstrated in peripheral blood could contribute to the amplified and prolonged immune response that characterizes sarcoidosis. However, this deficiency was not confirmed yet at the level of pulmonary invariant NKT cell. Consequently, we showed that clinical categories known to have better outcomes (ie, patients with Löfgren syndrome) tend to have higher frequencies of BALF CD3+CD16/56+ NKT cells. Nevertheless, comparable low frequencies of pulmonary CD3+CD16/56+ NKT cells were also observed in our patients with other types of ILDs such as idiopathic interstitial pneumonias or ILD due to connective tissue disorders (unpublished data).

In summary, these studies demonstrate elevated frequencies of NKT cells in the lungs of patient with hypersensitivity pneumonitis in comparison to other study cases of ILDs. Therefore, the assessing of NKT cells in BALF might be a helpful adjunct in diagnosis of patients with hypersensitivity pneumonitis. We also found that a major subset of NKT cells were CD8+CD56+ cells with potent cytolytic and immunoregulation functions, which suggest a new insight in pathogenesis of hypersensitivity pneumonitis.

Footnotes

Abbreviations: BALF = BAL fluid; IFN = interferon; ILD = interstitial lung disease; NK = natural killer; NKT = natural killer T; TCR = T-cell receptor; Th1 = T-helper type 1

This work was performed at University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.

The authors have no conflicts of interest to disclose.

Received for publication January 23, 2007. Accepted for publication June 5, 2007.

References

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