Single-cell RNA sequencing unravels T cell exhaustion underlying the chronicity of chromoblastomycosis

<h4>Introduction</h4>Chromoblastomycosis (CBM) is a chronic, neglected tropical fungal infection. Its immunopathogenesis, particularly the mechanism underlying its chronicity, remains poorly understood.<h4>Methods</h4>We performed single-cell RNA sequencing (scRNA-seq) on lesional skin from a CBM patient, followed by comprehensive bioinformatics analyses. We then used multiplex immunofluorescence (mIF) to validate CD4⁺ T cell exhaustion in CBM patient lesions and the mouse model of <i>Fonsecaea pedrosoi</i> infection.<h4>Results</h4>We identified a significantly expanded population of exhausted CD4⁺ T cells within the patient's lesions, which exhibited high co-expression of inhibitory receptors (PD-1, TIM-3, LAG-3) and functional impairment. Trajectory inference suggested a differentiation path from naive towards exhaustion within the chronic inflammatory environment. Cell-cell communication analysis implicated monocytes/macrophages (MoMacs) as key drivers of this process via persistent antigen presentation and ligand-receptor interactions such as CTLA4-CD80/86 and LGALS9-CD44. The accumulation of exhausted CD4⁺ T cells was confirmed in human CBM lesions by multiplex immunofluorescence (mIF), and the progressive development of exhaustion was recapitulated in the mouse model of <i>Fonsecaea pedrosoi</i> infection.<h4>Discussion</h4>Our findings establish CD4⁺ T cell exhaustion as an important mechanism underlying the chronicity of chromoblastomycosis, revealing a new immunopathological perspective for this neglected disease.