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. 2010 Mar;104(3):454-62.
doi: 10.1016/j.rmed.2009.10.004. Epub 2009 Oct 31.

T lymphocyte subset abnormalities in the blood and lung in pulmonary arterial hypertension

E D Austin  1 , M T Rock, C A Mosse, C L Vnencak-Jones, S M Yoder, I M Robbins, J E Loyd, B O Meyrick
Affiliations

T lymphocyte subset abnormalities in the blood and lung in pulmonary arterial hypertension

E D Austin et al. Respir Med. 2010 Mar.

Abstract

Rationale: Mounting data suggest that immune cell abnormalities participate in the pathogenesis of pulmonary arterial hypertension (PAH).

Objective: To determine whether the T lymphocyte subset composition in the systemic circulation and peripheral lung is altered in PAH.

Methods: Flow cytometric analyses were performed to determine the phenotypic profile of peripheral blood lymphocytes in idiopathic PAH (IPAH) patients (n=18) and healthy controls (n=17). Immunocytochemical analyses of lymphocytes and T cell subsets were used to examine lung tissue from PAH patients (n=11) and controls (n=11).

Measurements and main results: IPAH patients have abnormal CD8+ T lymphocyte subsets, with a significant increase in CD45RA+ CCR7- peripheral cytotoxic effector-memory cells (p=0.02) and reduction of CD45RA+ CCR7+ naive CD8+ cells versus controls (p=0.001). Further, IPAH patients have a higher proportion of circulating regulatory T cells (T(reg)) and 4-fold increases in the number of CD3+ and CD8+ cells in the peripheral lung compared with controls (p<0.01).

Conclusions: Alterations in circulating T cell subsets, particularly CD8+ T lymphocytes and CD4+ T(reg), in patients with PAH suggest that a dysfunctional immune system contributes to disease pathogenesis. A preponderance of CD3+ and CD8+ T lymphocytes in the peripheral lung of PAH patients supports this concept.

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Conflict of interest statement

CONFLICT OF INTEREST NOTIFICATION PAGE: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Figures

Figure 1
Figure 1. Circulating blood CD8+ T lymphocyte subsets are abnormal in IPAH
Circulating blood lymphocytes were analyzed by flow cytometry in IPAH and control subjects. Patients with IPAH have a significantly higher percentage of CD45RA+CCR7- CD8+ T lymphocytes (left box) and a significantly lower percentage of CD45RA+CCR7+ CD8+ T lymphocytes. (A) Box plots demonstrate the median value (line), and inter-quartile range for each group (grey boxplots are IPAH group and open boxplots are Control group; note that values in the text are given as mean ± S.D.). (B) Representative flow cytometric dot plots from an IPAH patient (left panel) and a healthy control (right panel). CD8+ T cells were gated based on CCR7 and CD45RA expression. The numbers in the corners indicate the percentages of cells within that particular quadrant.
Figure 2
Figure 2. Elevated circulating blood CD4+ regulatory T lymphocytes (Tregs) in IPAH
(A) Circulating blood lymphocytes were analyzed by flow cytometry in IPAH and control subjects. Patients with IPAH have a significantly higher percentage of CD25+FoxP3+ Tregs and CD25+FoxP3+CD127low Tregs. Box plots demonstrate the median value (line), and inter-quartile range for each group (grey boxplots are IPAH group and open boxplots are Control group; note that values in the text are given as mean ± S.D.). (B) Representative dot plots from an IPAH patient and healthy control (upper panels). CD4+ T cells were gated based on CD25 and FoxP3 expression. The numbers indicate the percentages of CD25+FoxP3+ cells within the gated region. Histogram (lower panels) to illustrate low CD127 expression on Tregs (grey) compared to total CD4+ T cell population (black).
Figure 2
Figure 2. Elevated circulating blood CD4+ regulatory T lymphocytes (Tregs) in IPAH
(A) Circulating blood lymphocytes were analyzed by flow cytometry in IPAH and control subjects. Patients with IPAH have a significantly higher percentage of CD25+FoxP3+ Tregs and CD25+FoxP3+CD127low Tregs. Box plots demonstrate the median value (line), and inter-quartile range for each group (grey boxplots are IPAH group and open boxplots are Control group; note that values in the text are given as mean ± S.D.). (B) Representative dot plots from an IPAH patient and healthy control (upper panels). CD4+ T cells were gated based on CD25 and FoxP3 expression. The numbers indicate the percentages of CD25+FoxP3+ cells within the gated region. Histogram (lower panels) to illustrate low CD127 expression on Tregs (grey) compared to total CD4+ T cell population (black).
Figure 3
Figure 3. Elevated CD3+ and CD8+ lymphocytes in the peripheral lung of patients with PAH compared to controls
(A) Counts of lymphocyte subsets related to total number of nuclei per field in the peripheral lung of PAH patients (grey blocks) and controls (open blocks). Box plots demonstrate the median value (line), and inter-quartile range for each group; * p<0.01 compared to controls. (B) Peripheral lung from a patient with PAH and a control showing increased numbers of CD3+ and CD8+ lymphocytes in the PAH patient. Line in lower right micrograph = 100 µm.
Figure 3
Figure 3. Elevated CD3+ and CD8+ lymphocytes in the peripheral lung of patients with PAH compared to controls
(A) Counts of lymphocyte subsets related to total number of nuclei per field in the peripheral lung of PAH patients (grey blocks) and controls (open blocks). Box plots demonstrate the median value (line), and inter-quartile range for each group; * p<0.01 compared to controls. (B) Peripheral lung from a patient with PAH and a control showing increased numbers of CD3+ and CD8+ lymphocytes in the PAH patient. Line in lower right micrograph = 100 µm.
See this image and copyright information in PMC

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