LRBA deficiency impairs autophagy and contributes to enhanced antigen presentation and T-cell dysregulation.

Abstract

Reduced autophagy is associated with the aberrant humoral response observed in lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency; however, the molecular mechanisms and their impact on T-cell responses remain poorly understood. We identify two novel LRBA interactors, phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4) and FYVE And Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1), which each play key roles in autophagy. PIK3R4 facilitates the production of phosphatidylinositol-3 phosphate (PI(3)P) that promotes autophagosome formation and autophagosome-lysosome fusion, whereas FYCO1 supports autophagosome movement. LRBA-knockout (KO) cells show impaired PI(3)P production, reduced autophagosome-lysosome fusion, accumulation of enlarged autophagosomes, and decreased cargo degradation. In line with the role of autophagy as a major degradation system for MHC-II loading and antigen presentation, we observe increased numbers of MHC class II and LC3 vesicles, along with enhanced antigen presentation in absence of LRBA, resulting in a higher production of proinflammatory cytokines from T cells in vitro. Our work suggests a novel biological role of LRBA controlling antigen presentation and T-cell responses by positively regulating autophagy, which may contribute to T-cell immune dysregulation observed in LRBA-deficient patients.