Sialophorin is necessary for vaccine-induced CD8+ T cell responses and immunity against lethal fungal pneumonia in CD4+ T-cell deficient hosts

Abstract

Abstract Increased opportunistic fungal infections in immunocompromised patients and lack of effective therapeutic modalities caused millions of deaths worldwide. Further, there are no licensed vaccines available for such and for immune-sufficient individuals. Previously, we have shown that in the absence of CD4+ T cells, vaccine-induced CD8+ T cells can mount sterilizing fungal immunity. However, molecules that have an immunomodulatory effect on CD8+ T cells are still to be explored. Using a mouse model of CD4+ T cell lymphopenia and experimental fungal vaccine, we demonstrate that Sialophorin (CD43), a molecule deficient in WAS patients, plays a critical role in mounting anti-fungal immunity. Genetic ablation of CD43 resulted in blunted CD8+ T cell responses associated with reduced expression of prototypic lineage-specific transcription factors following vaccination. Cell-intrinsic expression of CD43 on CD8+ T cells was indispensable for their expansion. Poor vaccine-induced effector CD8+ T cell responses under CD43-deficiency caused the failure to control fungal pneumonia following lethal challenge, independent of trafficking defect of the CD43-deficient effector cells. Further, we demonstrate antigen-specific CD8+ T cells preferentially expressed glycosylated-CD43. Notably, the numbers of glycosylated-CD43+ CD8+ T cells were directly correlated with vaccine-immunity. Thus, the glycosylated-CD43 expression on the CD8+ T cells could serve as a biological marker of vaccine efficacy and clinical outcome of fungal pneumonia. In conclusion, we report that CD43 is required for effective vaccine-immunity against lethal fungal pneumonia, and glycosylated-CD43 could be a novel phenotypic T-cell marker of fungal immunity.