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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.


Proportion of regulatory T cells (Tregs) within total lung CD4+ T cells. Tregs were identified as CD3+CD4+FoxP3+CD127− cells (A). The proportion of Tregs does not differ between IPF and non-IPF controls (GOH) (B). Significance determined by Mann–Whitney test.
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Figure 4: Proportion of regulatory T cells (Tregs) within total lung CD4+ T cells. Tregs were identified as CD3+CD4+FoxP3+CD127− cells (A). The proportion of Tregs does not differ between IPF and non-IPF controls (GOH) (B). Significance determined by Mann–Whitney test.

Mentions: Similar to lung tissue, CCR4+ CD4+ T cells in the LLNs were increased (4.61%; range, 2.39–9.98%) compared to control LLNs (2.20%; range, 0.41–6.73%; p = 0.036) (Figure 3D). Although the CCR6+ CD4+ T cells were not significantly different between the two groups, there was a trend toward decreased percentages in the IPF LLNs. However, unlike CD4+ T cells within the lungs, the proportion of CXCR3+ CD4+ T cells was higher in IPF LLNs (13.60%; range, 5.80–26.90%) compared to controls (6.43%; range, 1.00–15.40%; p = 0.036). No differences in the percentages of CCR7+ CD4+ T cells were found in the lungs or LLN (Figure S4 in Supplementary Material). When focusing only on T cells positive for any of the three chemokine receptors, CXCR3+ CD4+ T cells constituted the greatest percentage in IPF LLNs, while CCR6+ CD4+ T cells constituted the greatest percentage in controls (Figures 3E,F). CCR4 is a marker of both conventional and regulatory T cells (Tregs). However, no differences were found in Tregs proportions (p = 0.181) (Figure 4) suggesting that the increase in CCR4+ CD4+ T cells in the lungs is not primarily due to increased Tregs.


Skewed Lung CCR4 to CCR6 CD4 + T Cell Ratio in Idiopathic Pulmonary Fibrosis Is Associated with Pulmonary Function
Proportion of regulatory T cells (Tregs) within total lung CD4+ T cells. Tregs were identified as CD3+CD4+FoxP3+CD127− cells (A). The proportion of Tregs does not differ between IPF and non-IPF controls (GOH) (B). Significance determined by Mann–Whitney test.
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Figure 4: Proportion of regulatory T cells (Tregs) within total lung CD4+ T cells. Tregs were identified as CD3+CD4+FoxP3+CD127− cells (A). The proportion of Tregs does not differ between IPF and non-IPF controls (GOH) (B). Significance determined by Mann–Whitney test.
Mentions: Similar to lung tissue, CCR4+ CD4+ T cells in the LLNs were increased (4.61%; range, 2.39–9.98%) compared to control LLNs (2.20%; range, 0.41–6.73%; p = 0.036) (Figure 3D). Although the CCR6+ CD4+ T cells were not significantly different between the two groups, there was a trend toward decreased percentages in the IPF LLNs. However, unlike CD4+ T cells within the lungs, the proportion of CXCR3+ CD4+ T cells was higher in IPF LLNs (13.60%; range, 5.80–26.90%) compared to controls (6.43%; range, 1.00–15.40%; p = 0.036). No differences in the percentages of CCR7+ CD4+ T cells were found in the lungs or LLN (Figure S4 in Supplementary Material). When focusing only on T cells positive for any of the three chemokine receptors, CXCR3+ CD4+ T cells constituted the greatest percentage in IPF LLNs, while CCR6+ CD4+ T cells constituted the greatest percentage in controls (Figures 3E,F). CCR4 is a marker of both conventional and regulatory T cells (Tregs). However, no differences were found in Tregs proportions (p = 0.181) (Figure 4) suggesting that the increase in CCR4+ CD4+ T cells in the lungs is not primarily due to increased Tregs.

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.