Exhausted T cell phenotypes in disseminated coccidioidomycosis

Area of Science:

• Immunology
• Infectious Diseases
• Mycology

Background:

• Coccidioidomycosis, or Valley Fever, ranges from mild to life-threatening disseminated disease (DCM).
• While some immune deficits are known, specific defects in DCM are often unclear.
• Chronic antigen exposure may lead to T cell exhaustion in DCM.

Purpose of the Study:

• To investigate T cell phenotypes and responses in patients with coccidioidomycosis.
• To explore the role of T cell exhaustion in the dissemination of Coccidioides infection.
• To assess the potential of PD-1 blockade as a therapeutic strategy.

Main Methods:

• Flow cytometry to characterize T cell phenotypes.
• Activation-Induced Marker (AIM) assay to measure Coccidioides-specific T cell responses.
• In vitro PD-1 blockade assay to evaluate T cell function.

Main Results:

• Male sex was associated with increased risk of disseminated coccidioidomycosis.
• Fewer disseminated coccidioidomycosis patients showed Coccidioides-specific T cell responses compared to uncomplicated Valley Fever patients, especially within the first year of diagnosis.
• DCM patients with detectable responses exhibited T cell exhaustion, marked by elevated PD-1 expression.
• In vitro PD-1 blockade enhanced T cell IFNγ production in DCM subjects.

Conclusions:

• Impaired antigen-specific T cell activity may contribute to coccidioidomycosis dissemination.
• T cell exhaustion, indicated by PD-1 expression, is a feature of disseminated disease.
• PD-1 blockade shows promise as an adjunctive therapy for disseminated coccidioidomycosis.