Although fibrotic disorders are frequently assumed to be linked to T H2 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 T H2 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. T H2 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.