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Skewed Lung CCR4 to CCR6 CD4 + T Cell Ratio in Idiopathic Pulmonary Fibrosis Is Associated with Pulmonary Function

View Article: PubMed Central - PubMed

ABSTRACT

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease. While it has been suggested that T cells may contribute to IPF pathogenesis, these studies have focused primarily on T cells outside of the pulmonary interstitium. Thus, the role of T cells in the diseased lung tissue remains unclear.

Objective: To identify whether specific CD4+ T cell subsets are differentially represented in lung tissue from patients with IPF.

Methods: CD4+ T cell subsets were measured in lung tissue obtained from patients with IPF at the time of lung transplantation, and from age- and gender-matched organ donors with no known lung disease. Subsets were identified by their surface expression of CCR4, CCR6, and CXCR3 chemokine receptors. CD4+ T cell subsets were correlated with measurements of lung function obtained prior to transplantation.

Results: Compared to controls, IPF patients had a higher proportion of lung CD4+ T cells, a higher proportion of CCR4+ CD4+ T cells, and a lower proportion of CCR6+ CD4+ T cells. The increase in CCR4+ CD4+ T cells in IPF lung tissue was not due to increased Tregs. Intriguingly, the increase in the ratio of CCR4+ cells to CCR6+ cells correlated significantly with better lung function.

Conclusion: Our findings suggest a new paradigm that not all T cell infiltrates in IPF lungs are detrimental, but instead, specialized subsets may actually be protective. Thus, augmentation of the chemokines that recruit protective T cells, while blocking chemokines that recruit detrimental T cells, may constitute a novel approach to IPF therapy.

No MeSH data available.


CD4+ T cells constitute a greater percentage of tissue cells in IPF lungs and lung lymph nodes (LLN) than in non-IPF controls (GOH). CD4+ T cells are increased in IPF lungs (A); and LLN (B,E) compared to non-IPF controls. However, CD8+ T cell percentages are increased in IPF lungs (C), but similar in the LLN (D,E); while CD4:CD8 ratios are similar (F). Significance determined by Mann–Whitney test. Mean values depicted (E).
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Figure 1: CD4+ T cells constitute a greater percentage of tissue cells in IPF lungs and lung lymph nodes (LLN) than in non-IPF controls (GOH). CD4+ T cells are increased in IPF lungs (A); and LLN (B,E) compared to non-IPF controls. However, CD8+ T cell percentages are increased in IPF lungs (C), but similar in the LLN (D,E); while CD4:CD8 ratios are similar (F). Significance determined by Mann–Whitney test. Mean values depicted (E).

Mentions: Substantial variations in the proportions of circulating CD4+ T cells in IPF patients may not accurately reflect their proportions in lung tissue (27, 30). To elucidate the pattern of CD4+ T cell distribution in IPF lungs and LLN, we analyzed the absolute percentages of CD4+ T cells and CD8+ T cells in tissues from subjects with IPF and from controls. The median percentage of CD4+ T cells in lung tissue of subjects with IPF (5.40%; range, 2.17–19.10%) was significantly higher than in controls (1.53%; range, 0.37–4.70%; p = 0.0002) (Figure 1A). Similarly, the median percentage of CD4+ T cells in LLN of subjects with IPF (34.80%; range, 18.50–46.80%) was significantly higher than in controls (20.30%; range, 10.70–37.60%; p = 0.007) (Figure 1B). While no significant difference was observed in the percentages of CD8+ T cells in LLNs of subjects with IPF compared to controls (p = 0.523), the median percentage of CD8+ T cells in lung tissue of subjects with IPF (5.95%; range, 1.27–8.90%) was higher than in controls (1.18%; range, 0.75–9.13%; p = 0.021) (Figures 1C,D). The dramatic increase found in the proportion of CD4+ T cells was likely not due to a decrease in another cell type since the CD4+ T cells were only a small fraction of total lung cells (Figure 1E). No significant difference was observed in the CD4:CD8 T cell ratio in the lungs (p = 0.467) or LLNs (p = 0.131) (Figure 1F). While we were unable to obtain blood from our controls, the IPF patient’s blood had significantly greater CD4+ T cells (35.95%; range, 24.70–44.20%) than CD8+ T cells (19.99%; range, 10.50–33.10%; p = 0.002), and a CD4:CD8 ratio of 2.15 (range, 0.81–3.58). Thus, the percentages of CD4+ T cells are dramatically increased in both the lung and LLNs of IPF patients, suggesting that they either undergo expansion specifically in IPF tissues, or are highly recruited from the circulating pool of CD4+ T cells.


Skewed Lung CCR4 to CCR6 CD4 + T Cell Ratio in Idiopathic Pulmonary Fibrosis Is Associated with Pulmonary Function
CD4+ T cells constitute a greater percentage of tissue cells in IPF lungs and lung lymph nodes (LLN) than in non-IPF controls (GOH). CD4+ T cells are increased in IPF lungs (A); and LLN (B,E) compared to non-IPF controls. However, CD8+ T cell percentages are increased in IPF lungs (C), but similar in the LLN (D,E); while CD4:CD8 ratios are similar (F). Significance determined by Mann–Whitney test. Mean values depicted (E).
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Figure 1: CD4+ T cells constitute a greater percentage of tissue cells in IPF lungs and lung lymph nodes (LLN) than in non-IPF controls (GOH). CD4+ T cells are increased in IPF lungs (A); and LLN (B,E) compared to non-IPF controls. However, CD8+ T cell percentages are increased in IPF lungs (C), but similar in the LLN (D,E); while CD4:CD8 ratios are similar (F). Significance determined by Mann–Whitney test. Mean values depicted (E).
Mentions: Substantial variations in the proportions of circulating CD4+ T cells in IPF patients may not accurately reflect their proportions in lung tissue (27, 30). To elucidate the pattern of CD4+ T cell distribution in IPF lungs and LLN, we analyzed the absolute percentages of CD4+ T cells and CD8+ T cells in tissues from subjects with IPF and from controls. The median percentage of CD4+ T cells in lung tissue of subjects with IPF (5.40%; range, 2.17–19.10%) was significantly higher than in controls (1.53%; range, 0.37–4.70%; p = 0.0002) (Figure 1A). Similarly, the median percentage of CD4+ T cells in LLN of subjects with IPF (34.80%; range, 18.50–46.80%) was significantly higher than in controls (20.30%; range, 10.70–37.60%; p = 0.007) (Figure 1B). While no significant difference was observed in the percentages of CD8+ T cells in LLNs of subjects with IPF compared to controls (p = 0.523), the median percentage of CD8+ T cells in lung tissue of subjects with IPF (5.95%; range, 1.27–8.90%) was higher than in controls (1.18%; range, 0.75–9.13%; p = 0.021) (Figures 1C,D). The dramatic increase found in the proportion of CD4+ T cells was likely not due to a decrease in another cell type since the CD4+ T cells were only a small fraction of total lung cells (Figure 1E). No significant difference was observed in the CD4:CD8 T cell ratio in the lungs (p = 0.467) or LLNs (p = 0.131) (Figure 1F). While we were unable to obtain blood from our controls, the IPF patient’s blood had significantly greater CD4+ T cells (35.95%; range, 24.70–44.20%) than CD8+ T cells (19.99%; range, 10.50–33.10%; p = 0.002), and a CD4:CD8 ratio of 2.15 (range, 0.81–3.58). Thus, the percentages of CD4+ T cells are dramatically increased in both the lung and LLNs of IPF patients, suggesting that they either undergo expansion specifically in IPF tissues, or are highly recruited from the circulating pool of CD4+ T cells.

View Article: PubMed Central - PubMed

ABSTRACT

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease. While it has been suggested that T cells may contribute to IPF pathogenesis, these studies have focused primarily on T cells outside of the pulmonary interstitium. Thus, the role of T cells in the diseased lung tissue remains unclear.

Objective: To identify whether specific CD4+ T cell subsets are differentially represented in lung tissue from patients with IPF.

Methods: CD4+ T cell subsets were measured in lung tissue obtained from patients with IPF at the time of lung transplantation, and from age- and gender-matched organ donors with no known lung disease. Subsets were identified by their surface expression of CCR4, CCR6, and CXCR3 chemokine receptors. CD4+ T cell subsets were correlated with measurements of lung function obtained prior to transplantation.

Results: Compared to controls, IPF patients had a higher proportion of lung CD4+ T cells, a higher proportion of CCR4+ CD4+ T cells, and a lower proportion of CCR6+ CD4+ T cells. The increase in CCR4+ CD4+ T cells in IPF lung tissue was not due to increased Tregs. Intriguingly, the increase in the ratio of CCR4+ cells to CCR6+ cells correlated significantly with better lung function.

Conclusion: Our findings suggest a new paradigm that not all T cell infiltrates in IPF lungs are detrimental, but instead, specialized subsets may actually be protective. Thus, augmentation of the chemokines that recruit protective T cells, while blocking chemokines that recruit detrimental T cells, may constitute a novel approach to IPF therapy.

No MeSH data available.