Robust T cell responses to aspergillosis in chronic granulomatous disease: Implications for immunotherapy

Summary: Chronic granulomatous disease (CGD) patients are highly susceptible to invasive aspergillosis and might benefit from aspergillus-specific T cell immunotherapy, which has shown promise in treating those with known T cell defects such as haematopoietic stem cell transplant (HSCT) recipients. But whether such T cell defects contribute to increased risks for aspergillus infection in CGD is unclear. Hence, we set out to characterize the aspergillus-specific T cell response in CGD. In murine CGD models and in patients with CGD we showed that the CD4⁺ T cell responses to aspergillus were unimpaired: aspergillus-specific T cell frequencies were even elevated in CGD mice (P<0·01) and humans (P=0·02), compared to their healthy counterparts. CD4-depleted murine models suggested that the role of T cells might be redundant because resistance to aspergillus infection was conserved in CD4⁺ T cell-depleted mice, similar to wild-type animals. In contrast, mice depleted of neutrophils alone or neutrophils and CD4⁺ T cells developed clinical and pathological evidence of pulmonary aspergillosis and increased mortality (P<0·05 compared to non-depleted animals). Our findings that T cells in CGD have a robust aspergillus CD4⁺ T cell response suggest that CD4⁺ T cell-based immunotherapy for this disease is unlikely to be beneficial.