CD4+CTLs in Fibrosing Mediastinitis Linked to Histoplasma capsulatum

Abstract

Although fibrotic disorders are frequently assumed to be linked to TH2 cells, quantitative tissue interrogation studies have rarely been performed to establish this link and certainly many fibrotic diseases do not fall within the type 2/allergic disease spectrum. We have previously linked two human autoimmune fibrotic diseases, IgG4-related disease and systemic sclerosis, to the clonal expansion and lesional accumulation of CD4+CTLs. In both these diseases TH2 cell accumulation was found to be sparse. Fibrosing mediastinitis linked to Histoplasma capsulatum infection histologically resembles IgG4-related disease in terms of the inflammatory infiltrate and fibrosis, and it provides an example of a fibrotic disease of infectious origin in which the potentially profibrotic T cells may be induced and reactivated by fungal Ags. We show in this study that, in this human disease, CD4+CTLs accumulate in the blood, are clonally expanded, infiltrate into disease lesions, and can be reactivated in vitro by H. capsulatum Ags. TH2 cells are relatively sparse at lesional sites. These studies support a general role for CD4+CTLs in inflammatory fibrosis and suggest that fibrosing mediastinitis is an Ag-driven disease that may provide important mechanistic insights into the pathogenesis of idiopathic fibrotic diseases.

Temporal changes in T cell subsets and expansion of cytotoxic CD4+ T cells in the lungs in severe COVID-19

“…5 A, B). CD4 + CTLs expand in many human fibrotic diseases and secrete cytokines [ [46] , [47] , [48] , [49] ]. The late influx of CD4 + CTLs and the clearance of virus may be linked to both an increase in apoptotic death of infected cells ( Fig.…”

“…The increase in inflammation that accompanies the late surge in CD4 + CTLs may potentially contribute to viral clearance, but this surge may also have negative consequences. CD4 + CTLs can, in some disease contexts, possibly provide the adaptive immune trigger for fibrosis [ [46] , [47] , [48] , [49] ]. Given the abundance of macrophages in the lungs, the studies on bronchoalveolar lavage derived cells that suggest that infected macrophages induce chemoattractant to attract T cells and the potential contribution of both these cell types to the fibrosis seen in COVID-19, the possibility that these cells might also contribute in some patients to the Post-Acute Sequelae of SARS-CoV-2 (PASC) should be kept in mind.…”

Rapamycin improves Graves’ orbitopathy by suppressing CD4+ cytotoxic T lymphocytes

“…The latter, closely associated with an accumulation of CD4 + CTLs in lesions, led to endothelial cell apoptosis and tissue fibrosis ( 23 , 24 ). Antigen-reactivated CD4 + CTLs also infiltrate lesions in fibrosing mediastinitis and drive inflammatory fibrosis ( 37 ). The results of these studies illustrated the pathogenicity of CD4 + CTLs in the process of immune-mediated inflammatory fibrosis in general and also imply that CD4 + CTLs could be potential treatment targets.…”

Immune dysregulation in immunoglobulin G4–related disease

“…Our current results in combination with our recent studies on another fibrotic disease, systemic sclerosis [46] suggest a model that may mechanistically unify clinically distinct autoimmune fibrotic disorders. Others have provided evidence for CD4 + CTLs being of relevance to fibrosis in Grave’s orbitopathy [47] , Histoplasma capsulatum infection [48] , and COVID-19 infection [49] .…”