Functional Diversity of T-Cell Subpopulations in Subacute and Chronic Hypersensitivity Pneumonitis

Abstract

Rationale: Hypersensitivity pneumonitis (HP) exhibits a diverse outcome. Patients with acute/subacute HP usually improve, whereas patients with chronic disease often progress to fibrosis. However, the mechanisms underlying this difference are unknown. Objectives: To examine the T-cell profile from patients with subacute HP and chronic HP. Methods: T cells were obtained by bronchoalveolar lavage from 25 patients with subacute HP, 30 patients with chronic HP, and 8 control subjects. T-cell phenotype and functional profile were evaluated by flow cytometry, cytometric bead array, and immunohistochemistry. Measurements and Main Results: Patients with chronic HP showed higher CD4(+):CD8(+) ratio (median, 3.05

range, 0.3-15

subacute HP: median, 1.3

range, 0.1-10

control: median, 1.3

range, 0.7-2.0

P < 0.01), and a decrease of gamma delta T cells (median, 2.0

range, 0.5-3.4, subacute HP: median, 10

range, 4.8-17

control: median, 15

range, 5-19

P < 0.01). Patients with chronic HP exhibited an increase in the terminally differentiated memory CD4(+) and CD8(+) T-cell subsets compared with patients with subacute HP (P < 0.05). However, memory cells from chronic HIP showed lower IFN-gamma production and decreased cytotoxic activity by CD8(+) T lymphocytes. Chronic HP displayed a Th2-like phenotype with increased CXCR4 expression (median, 6%

range, 1.7-36, vs. control subjects: median, 0.7%

range, 0.2-1.4

and subacute HP: median, 2.2%

range, 0.1-5.3

P < 0.01), and decreased CXCR3 expression (median, 4.3%

range, 1.4-25%, vs. subacute HP: median, 37%

range, 4.9-78%

P < 0.01). Likewise, supernatants from antigen-specific-stimulated cells from chronic HP produced higher levels of IL-4 (80 +/- 63 pg/ml vs. 25 +/- 7 pg/ml

P < 0.01), and lower levels of IFN-gamma (3,818 +/- 1671 pg/ml vs. 100 61 pg/ml

P < 0.01) compared with subacute HP. Conclusions: Our findings indicate that patients with chronic HP lose effector T-cell function and exhibit skewing toward Th2 activity, which may be implicated in the fibrotic response that characterizes this clinical form.