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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.


Correlation of FVC and DLCO with CCR4+ CCR6− percent of CD4+ T cells and CCR6+ (CXCR3−) percent of CD4+ T cells in the lungs at time of lung explant. Lung CCR4+CCR6− percent of CD4+ T cells correlates with percentage forced vital capacity (FVC%) (r = 0.646; p = 0.061) (A); but not percentage diffusion capacity for carbon monoxide (DLCO%) (r = 0.555; p = 0.121) (B). Lung CCR6+ (CXCR3−) percent of CD4+ T cells does not correlate with FVC% (r = 0.073; p = 0.853) (C); or DLCO% (r = 0.585; p = 0.031) (D). The ratio of lung CCR4+/CXCR3− strongly correlates with percentage forced vital capacity (FVC%) (r = 0.863; p = 0.003) (E); but not with DLCO% (r = 0.172; p = 0.658) (F).
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Figure 5: Correlation of FVC and DLCO with CCR4+ CCR6− percent of CD4+ T cells and CCR6+ (CXCR3−) percent of CD4+ T cells in the lungs at time of lung explant. Lung CCR4+CCR6− percent of CD4+ T cells correlates with percentage forced vital capacity (FVC%) (r = 0.646; p = 0.061) (A); but not percentage diffusion capacity for carbon monoxide (DLCO%) (r = 0.555; p = 0.121) (B). Lung CCR6+ (CXCR3−) percent of CD4+ T cells does not correlate with FVC% (r = 0.073; p = 0.853) (C); or DLCO% (r = 0.585; p = 0.031) (D). The ratio of lung CCR4+/CXCR3− strongly correlates with percentage forced vital capacity (FVC%) (r = 0.863; p = 0.003) (E); but not with DLCO% (r = 0.172; p = 0.658) (F).

Mentions: To determine whether the skewed populations of CD4+ T cells in the IPF lungs are related to disease pathogenesis, we evaluated whether the percentages of lung CCR4+ and CCR6+ CD4+ T cells correlated with pulmonary function in our IPF cohort. Pulmonary function indices utilized were the most recent pretransplant percent predicted FVC, and percent predicted diffusion capacity for carbon monoxide (DLCO). The FVC demonstrated a positive correlation with lung CCR4+ CD4+ T cells (r = 0.65) although this did not reach statistical significance (p = 0.06) (Figure 5A), while the DLCO demonstrated no significant correlation with lung CCR4+ CD4+ T cells (r = 0.56; p = 0.12) (Figure 5B). In contrast, the proportion of CCR6+ CD4+ T cells in lung tissue of IPF patients trended with DLCO (r = 0.58, p = 0.10), but not with FVC (r = 0.07; p = 0.85) (Figures 5C,D). No other CD4+ subset demonstrated significant correlation with FVC or DLCO. In contrast with the lungs, the CD4+ T cell subsets from LLN and blood did not correlate with lung function measures, suggesting that the lung CD4+ T cells are primarily involved in IPF pathogenesis (Table S1 in Supplementary Material).


Skewed Lung CCR4 to CCR6 CD4 + T Cell Ratio in Idiopathic Pulmonary Fibrosis Is Associated with Pulmonary Function
Correlation of FVC and DLCO with CCR4+ CCR6− percent of CD4+ T cells and CCR6+ (CXCR3−) percent of CD4+ T cells in the lungs at time of lung explant. Lung CCR4+CCR6− percent of CD4+ T cells correlates with percentage forced vital capacity (FVC%) (r = 0.646; p = 0.061) (A); but not percentage diffusion capacity for carbon monoxide (DLCO%) (r = 0.555; p = 0.121) (B). Lung CCR6+ (CXCR3−) percent of CD4+ T cells does not correlate with FVC% (r = 0.073; p = 0.853) (C); or DLCO% (r = 0.585; p = 0.031) (D). The ratio of lung CCR4+/CXCR3− strongly correlates with percentage forced vital capacity (FVC%) (r = 0.863; p = 0.003) (E); but not with DLCO% (r = 0.172; p = 0.658) (F).
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Figure 5: Correlation of FVC and DLCO with CCR4+ CCR6− percent of CD4+ T cells and CCR6+ (CXCR3−) percent of CD4+ T cells in the lungs at time of lung explant. Lung CCR4+CCR6− percent of CD4+ T cells correlates with percentage forced vital capacity (FVC%) (r = 0.646; p = 0.061) (A); but not percentage diffusion capacity for carbon monoxide (DLCO%) (r = 0.555; p = 0.121) (B). Lung CCR6+ (CXCR3−) percent of CD4+ T cells does not correlate with FVC% (r = 0.073; p = 0.853) (C); or DLCO% (r = 0.585; p = 0.031) (D). The ratio of lung CCR4+/CXCR3− strongly correlates with percentage forced vital capacity (FVC%) (r = 0.863; p = 0.003) (E); but not with DLCO% (r = 0.172; p = 0.658) (F).
Mentions: To determine whether the skewed populations of CD4+ T cells in the IPF lungs are related to disease pathogenesis, we evaluated whether the percentages of lung CCR4+ and CCR6+ CD4+ T cells correlated with pulmonary function in our IPF cohort. Pulmonary function indices utilized were the most recent pretransplant percent predicted FVC, and percent predicted diffusion capacity for carbon monoxide (DLCO). The FVC demonstrated a positive correlation with lung CCR4+ CD4+ T cells (r = 0.65) although this did not reach statistical significance (p = 0.06) (Figure 5A), while the DLCO demonstrated no significant correlation with lung CCR4+ CD4+ T cells (r = 0.56; p = 0.12) (Figure 5B). In contrast, the proportion of CCR6+ CD4+ T cells in lung tissue of IPF patients trended with DLCO (r = 0.58, p = 0.10), but not with FVC (r = 0.07; p = 0.85) (Figures 5C,D). No other CD4+ subset demonstrated significant correlation with FVC or DLCO. In contrast with the lungs, the CD4+ T cell subsets from LLN and blood did not correlate with lung function measures, suggesting that the lung CD4+ T cells are primarily involved in IPF pathogenesis (Table S1 in Supplementary Material).

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.