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Impaired survival of regulatory T cells in pulmonary sarcoidosis.

Broos CE, van Nimwegen M, Kleinjan A, ten Berge B, Muskens F, in 't Veen JC, Annema JT, Lambrecht BN, Hoogsteden HC, Hendriks RW, Kool M, van den Blink B - Respir. Res. (2015)

Bottom Line: Patients with pulmonary sarcoidosis (n = 58) were included at time of diagnosis.Rather, increased proportions of circulating Tregs were observed, most prominently in patients developing chronic disease.In untreated patients with active pulmonary sarcoidosis, Tregs show impaired survival and enhanced apoptotic susceptibility towards CD95L.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.

ABSTRACT

Background: Impaired regulatory T cell (Treg) function is thought to contribute to ongoing inflammatory responses in sarcoidosis, but underlying mechanisms remain unclear. Moreover, it is not known if increased apoptotic susceptibility of Tregs may contribute to an impaired immunosuppressive function in sarcoidosis. Therefore, the aim of this study is to analyze proportions, phenotype, survival, and apoptotic susceptibility of Tregs in sarcoidosis.

Methods: Patients with pulmonary sarcoidosis (n = 58) were included at time of diagnosis. Tregs were analyzed in broncho-alveolar lavage fluid and peripheral blood of patients and healthy controls (HC).

Results: In sarcoidosis patients no evidence was found for a relative deficit of Tregs, neither locally nor systemically. Rather, increased proportions of circulating Tregs were observed, most prominently in patients developing chronic disease. Sarcoidosis circulating Tregs displayed adequate expression of FoxP3, CD25 and CTLA4. Remarkably, in sarcoidosis enhanced CD95 expression on circulating activated CD45RO(+) Tregs was observed compared with HC, and proportions of these cells were significantly increased. Specifically sarcoidosis Tregs--but not Th cells--showed impaired survival compared with HC. Finally, CD95L-mediated apoptosis was enhanced in sarcoidosis Tregs.

Conclusion: In untreated patients with active pulmonary sarcoidosis, Tregs show impaired survival and enhanced apoptotic susceptibility towards CD95L. Increased apoptosis likely contributes to the insufficient immunosuppressive function of sarcoidosis Tregs. Further research into this field will help determine whether improvement of Treg survival holds a promising new therapeutic approach for chronic sarcoidosis patients.

No MeSH data available.


Related in: MedlinePlus

Adequate expression of FoxP3, CD25 and CTLA4 on sarcoidosis circulating Tregs. FoxP3, CD25 and CTLA4 expression was determined on circulating CD25int-highFoxP3high Tregs of HC and SRC patients by flow cytometry. a–c. Mean fluorescence intensity of FoxP3 (a), CD25 (b) and CTLA4 (c). Mean fluorescence intensity was standardized to average expression in healthy control peripheral blood cells. Statistics: Horizontal lines indicate the median and significance was determined using a Mann–Whitney U test, * p < 0.05 ** p < 0.01. FoxP3 forkhead box P3, CTLA4 cytotoxic T lymphocyte antigen 4, HC healthy control, SRC sarcoidosis
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Fig2: Adequate expression of FoxP3, CD25 and CTLA4 on sarcoidosis circulating Tregs. FoxP3, CD25 and CTLA4 expression was determined on circulating CD25int-highFoxP3high Tregs of HC and SRC patients by flow cytometry. a–c. Mean fluorescence intensity of FoxP3 (a), CD25 (b) and CTLA4 (c). Mean fluorescence intensity was standardized to average expression in healthy control peripheral blood cells. Statistics: Horizontal lines indicate the median and significance was determined using a Mann–Whitney U test, * p < 0.05 ** p < 0.01. FoxP3 forkhead box P3, CTLA4 cytotoxic T lymphocyte antigen 4, HC healthy control, SRC sarcoidosis

Mentions: We confirmed that PB-derived CD25+ Treg suppressive capacity on autologous Th proliferation and cytokine production was significantly less in sarcoidosis compared with healthy controls (Additional file 3: Figure S2). Circulating CD25int-highFoxP3high Tregs of patients showed a trend towards increased expression levels of FoxP3 (Fig. 2a). Furthermore, CD25 and CTLA4 expression (downstream molecules of FoxP3) were significantly increased on PB CD25int-highFoxP3high Tregs of sarcoidosis patients compared with healthy controls (Fig. 2b,c).Fig. 2


Impaired survival of regulatory T cells in pulmonary sarcoidosis.

Broos CE, van Nimwegen M, Kleinjan A, ten Berge B, Muskens F, in 't Veen JC, Annema JT, Lambrecht BN, Hoogsteden HC, Hendriks RW, Kool M, van den Blink B - Respir. Res. (2015)

Adequate expression of FoxP3, CD25 and CTLA4 on sarcoidosis circulating Tregs. FoxP3, CD25 and CTLA4 expression was determined on circulating CD25int-highFoxP3high Tregs of HC and SRC patients by flow cytometry. a–c. Mean fluorescence intensity of FoxP3 (a), CD25 (b) and CTLA4 (c). Mean fluorescence intensity was standardized to average expression in healthy control peripheral blood cells. Statistics: Horizontal lines indicate the median and significance was determined using a Mann–Whitney U test, * p < 0.05 ** p < 0.01. FoxP3 forkhead box P3, CTLA4 cytotoxic T lymphocyte antigen 4, HC healthy control, SRC sarcoidosis
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4574219&req=5

Fig2: Adequate expression of FoxP3, CD25 and CTLA4 on sarcoidosis circulating Tregs. FoxP3, CD25 and CTLA4 expression was determined on circulating CD25int-highFoxP3high Tregs of HC and SRC patients by flow cytometry. a–c. Mean fluorescence intensity of FoxP3 (a), CD25 (b) and CTLA4 (c). Mean fluorescence intensity was standardized to average expression in healthy control peripheral blood cells. Statistics: Horizontal lines indicate the median and significance was determined using a Mann–Whitney U test, * p < 0.05 ** p < 0.01. FoxP3 forkhead box P3, CTLA4 cytotoxic T lymphocyte antigen 4, HC healthy control, SRC sarcoidosis
Mentions: We confirmed that PB-derived CD25+ Treg suppressive capacity on autologous Th proliferation and cytokine production was significantly less in sarcoidosis compared with healthy controls (Additional file 3: Figure S2). Circulating CD25int-highFoxP3high Tregs of patients showed a trend towards increased expression levels of FoxP3 (Fig. 2a). Furthermore, CD25 and CTLA4 expression (downstream molecules of FoxP3) were significantly increased on PB CD25int-highFoxP3high Tregs of sarcoidosis patients compared with healthy controls (Fig. 2b,c).Fig. 2

Bottom Line: Patients with pulmonary sarcoidosis (n = 58) were included at time of diagnosis.Rather, increased proportions of circulating Tregs were observed, most prominently in patients developing chronic disease.In untreated patients with active pulmonary sarcoidosis, Tregs show impaired survival and enhanced apoptotic susceptibility towards CD95L.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.

ABSTRACT

Background: Impaired regulatory T cell (Treg) function is thought to contribute to ongoing inflammatory responses in sarcoidosis, but underlying mechanisms remain unclear. Moreover, it is not known if increased apoptotic susceptibility of Tregs may contribute to an impaired immunosuppressive function in sarcoidosis. Therefore, the aim of this study is to analyze proportions, phenotype, survival, and apoptotic susceptibility of Tregs in sarcoidosis.

Methods: Patients with pulmonary sarcoidosis (n = 58) were included at time of diagnosis. Tregs were analyzed in broncho-alveolar lavage fluid and peripheral blood of patients and healthy controls (HC).

Results: In sarcoidosis patients no evidence was found for a relative deficit of Tregs, neither locally nor systemically. Rather, increased proportions of circulating Tregs were observed, most prominently in patients developing chronic disease. Sarcoidosis circulating Tregs displayed adequate expression of FoxP3, CD25 and CTLA4. Remarkably, in sarcoidosis enhanced CD95 expression on circulating activated CD45RO(+) Tregs was observed compared with HC, and proportions of these cells were significantly increased. Specifically sarcoidosis Tregs--but not Th cells--showed impaired survival compared with HC. Finally, CD95L-mediated apoptosis was enhanced in sarcoidosis Tregs.

Conclusion: In untreated patients with active pulmonary sarcoidosis, Tregs show impaired survival and enhanced apoptotic susceptibility towards CD95L. Increased apoptosis likely contributes to the insufficient immunosuppressive function of sarcoidosis Tregs. Further research into this field will help determine whether improvement of Treg survival holds a promising new therapeutic approach for chronic sarcoidosis patients.

No MeSH data available.


Related in: MedlinePlus