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

¹ Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico; ² Hospital Universitario "Dr. José E. González," Monterrey, Nuevo León, México; ³ Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico; and ⁴ Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico

Correspondence and requests for reprints should be addressed to Moisés Selman, M.D., Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, Mexico DF, Mexico. E-mail: mselmanl{at}yahoo.com.mx

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 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 HP showed lower IFN- 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- (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.

Key Words: allergic alveolitis • cytotoxic • hypersensitivity pneumonitis • T cells • Th1/Th2 cells

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The mechanisms by which some patients with hypersensitivity pneumonitis progress to fibrosis are yet unclear. What This Study Adds to the Field This study demonstrates that patients with chronic hypersensitivity have different phenotypic/functional lung T-cell subsets compared with patients with subacute disease, likely associated with the fibrotic response.