Chronic Follicular Bronchiolitis Requires Antigen-Specific Regulatory T Cell Control To Prevent Fatal Disease Progression

Abstract

In order to study regulatory T (Treg) cell control of chronic autoimmunity in a lymphoreplete host, we created and characterized a new model of autoimmune lung inflammation that targets the medium and small airways. We generated transgenic mice that express a chimeric membrane protein consisting of hen egg lysozyme (mHEL) and a hemoglobin (Hb) epitope tag under the control of the Clara cell secretory protein (CCSP) promoter, which largely limited transgene expression to the respiratory bronchioles. When CCSP-mHEL/Hb transgenic mice were crossed to N3.L2 TCR transgenic mice that recognize the Hb epitope, the bigenic progeny developed dense, pseudo-follicular lymphocytic peribronchiolar infiltrates that resembled the histological pattern of follicular bronchiolitis. Aggregates of activated IFN-γ- and IL-17A-secreting CD4+ T cells as well as B cells surrounded the airways. Lung pathology was similar in Ifng−/− and Il17a−/− mice, indicating that either cytokine is sufficient to establish chronic disease. A large number of antigen-specific Treg cells accumulated in the lesions and Treg cell-depletion in the affected mice led to an interstitial spread of the disease that ultimately proved fatal. Thus Treg cells act to restrain autoimmune responses, resulting in an organized and controlled chronic pathological process rather than a progressive disease.

A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice

“…Although a reduction in Treg numbers and/or function has been implicated as an etiology of autoimmunity, increased numbers of Tregs have also been observed in several autoimmune diseases, suggesting that, in some instances, Treg expansion and/or induction may actually constrain disease progression ( 37 , 38 ). Indeed, in other models of organ-specific autoimmunity, partial Treg depletion promotes disease progression and death, supporting the importance of Treg presence at sites of inflammation ( 39 ). Data on human Tregs in disease are largely limited to peripheral blood specimens, as studying local Treg generation and enumeration in patients is often not feasible.…”

The Clinical Characteristics and Outcomes of Follicular Bronchiolitis in Chinese Adult Patients

“…Schmitt et al . proposed that Treg cells restrain autoimmune responses, resulting in an organized and controlled chronic pathological process rather than a progressive disease in a new model of autoimmune FB driven by a steady production of antigen-specific T cells 9 . Bezrodnik showed that FB may be a phenotype associated CD25 deficiency presenting homozygous missense mutation in the IL-2 receptor (CD25αR) in a female Argentine patient 10 .…”

A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFNγ to generate self-tolerance and prevent colitis

“…HD5-mHEL mice were created similarly to previously reported CCSP-mHEL/Hb transgenic mice 45 . A detailed description of the generation of this line all other lines used for breeding and adoptive transfer experiments can be found in the Supplemental Methods.…”

“…Isolated lymphocytes were stained using both surface marker and intracellular cytokine staining panels as previously described 45 . A four-laser custom LSRII was used to collect FACS data and FlowJo software was used for gating analysis.…”