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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.


Phenotypic distribution of CD4+ CCR6− T cells and CD4+ CCR6+ T cells differ across tissue locations. CCR6− blood cells have a predominant pattern of CCR4 expression (A,C) while CCR6− lung lymph nodes (LLN) cells have predominant pattern of CXCR3 expression (A,D). CCR6+ blood cells have reduced CXCR3 expression (B,E) while CCR6+ LLN cells have increased CXCR3 expression compared to blood (B,F). Peripheral blood of IPF subjects demonstrates higher proportion of CCR4+CCR6−CD4 T cells (C), but lower proportion of CCR6+CXCR3− cells when compared to the lungs (E). Significance determined by the Friedman non-parametric paired ANOVA with post hoc Dunn test.
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Figure 2: Phenotypic distribution of CD4+ CCR6− T cells and CD4+ CCR6+ T cells differ across tissue locations. CCR6− blood cells have a predominant pattern of CCR4 expression (A,C) while CCR6− lung lymph nodes (LLN) cells have predominant pattern of CXCR3 expression (A,D). CCR6+ blood cells have reduced CXCR3 expression (B,E) while CCR6+ LLN cells have increased CXCR3 expression compared to blood (B,F). Peripheral blood of IPF subjects demonstrates higher proportion of CCR4+CCR6−CD4 T cells (C), but lower proportion of CCR6+CXCR3− cells when compared to the lungs (E). Significance determined by the Friedman non-parametric paired ANOVA with post hoc Dunn test.

Mentions: Using an established gating strategy for blood CD4+ T cells (Figure S2 in Supplementary Material), CCR6, CCR4, and CXCR3 expression on CD4+ T cells was determined in these compartments (Figure 2). CCR4+ CD4+ T cells within the blood of our IPF cohort (mean, 17.63 ± 5.91%) was significantly higher than in the lung tissue (mean, 8.01 ± 5.23%; p = 0.0003) (Figures 2A,C). The proportion of CCR6+ CD4+ T cells within the blood of our IPF cohort (mean, 1.00 ± 0.42%) was significantly decreased when compared to the proportion of lung and LLN CCR6+ CD4+ T cells (mean, 6.83 ± 2.78%; and mean, 8.31 ± 1.84%; p = 0.0009, respectively) (Figures 2B,E). Unlike cells from the blood or lungs, LLN CD4+ T cells demonstrated a significantly higher expression of CXCR3 (Figures 2A,D). The proportion of CCR6+ CXCR3+ CD4+ T cells within the blood of our IPF cohort (mean, 0.22 ± 0.25%) was significantly decreased when compared to the proportion of lung and LLN CCR6+ CXCR3+ CD4+ T cells (mean, 3.43 ± 2.27%; and mean, 3.18 ± 1.00%; p = 0.0011, respectively) (Figures 2B,F). While we did not have access to blood from the control donors, between the lungs, and LLN from the control donors, there was only a small difference in the CXCR3+ CD4+ T cells (Figure S3 in Supplementary Material). Thus, substantial differences in chemokine receptor expression on CD4+ T cells were found, based on their tissue location.


Skewed Lung CCR4 to CCR6 CD4 + T Cell Ratio in Idiopathic Pulmonary Fibrosis Is Associated with Pulmonary Function
Phenotypic distribution of CD4+ CCR6− T cells and CD4+ CCR6+ T cells differ across tissue locations. CCR6− blood cells have a predominant pattern of CCR4 expression (A,C) while CCR6− lung lymph nodes (LLN) cells have predominant pattern of CXCR3 expression (A,D). CCR6+ blood cells have reduced CXCR3 expression (B,E) while CCR6+ LLN cells have increased CXCR3 expression compared to blood (B,F). Peripheral blood of IPF subjects demonstrates higher proportion of CCR4+CCR6−CD4 T cells (C), but lower proportion of CCR6+CXCR3− cells when compared to the lungs (E). Significance determined by the Friedman non-parametric paired ANOVA with post hoc Dunn test.
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Related In: Results  -  Collection

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Figure 2: Phenotypic distribution of CD4+ CCR6− T cells and CD4+ CCR6+ T cells differ across tissue locations. CCR6− blood cells have a predominant pattern of CCR4 expression (A,C) while CCR6− lung lymph nodes (LLN) cells have predominant pattern of CXCR3 expression (A,D). CCR6+ blood cells have reduced CXCR3 expression (B,E) while CCR6+ LLN cells have increased CXCR3 expression compared to blood (B,F). Peripheral blood of IPF subjects demonstrates higher proportion of CCR4+CCR6−CD4 T cells (C), but lower proportion of CCR6+CXCR3− cells when compared to the lungs (E). Significance determined by the Friedman non-parametric paired ANOVA with post hoc Dunn test.
Mentions: Using an established gating strategy for blood CD4+ T cells (Figure S2 in Supplementary Material), CCR6, CCR4, and CXCR3 expression on CD4+ T cells was determined in these compartments (Figure 2). CCR4+ CD4+ T cells within the blood of our IPF cohort (mean, 17.63 ± 5.91%) was significantly higher than in the lung tissue (mean, 8.01 ± 5.23%; p = 0.0003) (Figures 2A,C). The proportion of CCR6+ CD4+ T cells within the blood of our IPF cohort (mean, 1.00 ± 0.42%) was significantly decreased when compared to the proportion of lung and LLN CCR6+ CD4+ T cells (mean, 6.83 ± 2.78%; and mean, 8.31 ± 1.84%; p = 0.0009, respectively) (Figures 2B,E). Unlike cells from the blood or lungs, LLN CD4+ T cells demonstrated a significantly higher expression of CXCR3 (Figures 2A,D). The proportion of CCR6+ CXCR3+ CD4+ T cells within the blood of our IPF cohort (mean, 0.22 ± 0.25%) was significantly decreased when compared to the proportion of lung and LLN CCR6+ CXCR3+ CD4+ T cells (mean, 3.43 ± 2.27%; and mean, 3.18 ± 1.00%; p = 0.0011, respectively) (Figures 2B,F). While we did not have access to blood from the control donors, between the lungs, and LLN from the control donors, there was only a small difference in the CXCR3+ CD4+ T cells (Figure S3 in Supplementary Material). Thus, substantial differences in chemokine receptor expression on CD4+ T cells were found, based on their tissue location.

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.