Follicular Helper–like T Cells in the Lung Highlight a Novel Role of B Cells in Sarcoidosis

Abstract

Rationale

Pulmonary sarcoidosis is generally presumed to be a T-helper cell type 1– and macrophage-driven disease. However, mouse models have recently revealed that chronically inflamed lung tissue can also comprise T follicular helper (Tfh)-like cells and represents a site of active T-cell/B-cell cooperation.

Objectives

To assess the role of pulmonary Tfh- and germinal center–like lymphocytes in sarcoidosis.

Methods

BAL fluid, lung tissue, and peripheral blood samples from patients with sarcoidosis were analyzed by flow cytometry, immunohistology, RNA sequencing, and in vitro T-cell/B-cell cooperation assays for phenotypic and functional characterization of germinal center–like reactions in inflamed tissue.

Measurements and Main Results

We identified a novel population of Tfh-like cells characterized by high expression of the B helper molecules CD40L and IL-21 in BAL of patients with sarcoidosis. Transcriptome analysis further confirmed a phenotype that was both Tfh-like and tissue resident. BAL T cells provided potent help for B cells to differentiate into antibody-producing cells. In lung tissue, we observed large peribronchial infiltrates with T and B cells in close contact, and many IgA ⁺ plasmablasts. Most clusters were nonectopic; that is, they did not contain follicular dendritic cells. Patients with sarcoidosis also showed elevated levels of PD-1 ^high CXCR5 ⁻ CD40L ^high ICOS ^high Tfh-like cells, but not classical CXCR5 ⁺ Tfh cells, in the blood.

Conclusions

Active T-cell/B-cell cooperation and local production of potentially pathogenic antibodies in the inflamed lung represents a novel pathomechanism in sarcoidosis and should be considered from both diagnostic and therapeutic perspectives.