Open AccessFollicular Helper–like T Cells in the Lung Highlight a Novel Role of B Cells in Sarcoidosis
Author(s) -
Laura L. Bauer,
Lisa Jasmin Müller,
Sarah M. Volkers,
Frederik Heinrich,
MirFarzin Mashreghi,
Clemens Ruppert,
Leif E. Sander,
Andreas Hutloff
Publication year - 2021
Publication title -
american journal of respiratory and critical care medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.272
H-Index - 374
eISSN - 1535-4970
pISSN - 1073-449X
DOI - 10.1164/rccm.202012-4423oc
Subject(s) - germinal center , cxcr5 , immunology , medicine , cd40 , sarcoidosis , t cell , flow cytometry , interleukin 21 , population , antibody , follicular dendritic cells , b cell , lung , pathology , antigen presenting cell , cytotoxic t cell , biology , in vitro , immune system , biochemistry , environmental health
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.