BLOC1S1: An Unexpected Regulator of Th2 Cell-driven Inflammatory Responses

Abstract

Abstract BLOC1S1 is an adaptor protein that modulates endosome-lysosome function as a component of numerous multiprotein complexes. We postulated that its modulation in CD4 +T cells may help us uncover the role of endosome-lysosome biology in adaptive immunity. In primary CD4 +T cells BLOC1S1 cre-recombinase knockout resulted in the preferential induction of Th2 compared to Th1 and Th17 cytokine production following T cell receptor activation. As atopic dermatitis is an allergic inflammatory skin disease characterized by the production of the type 2 cytokines in the skin we evaluated the effect of CD4 +T cell BLOC1S1 KO vs controls in calcipotriol-induced atopic dermatitis in mice. The absence of BLOC1S1 exhibited exacerbated atopic dermatitis accompanied with significantly elevated plasma IgE, skin eosinophilia, elevated type 2 responses, and inflammatory pathology relative to wild-type mice. The transcription factor Gata-3 is expressed in Th2 but not Th1 cells and plays a critical role in Th2 differentiation and atopic dermatitis. BLOC1S1 deficient CD4 +T cells showed enhanced nuclear factor kB (NF-kB), Gata3 and LC3 positive autophagosomes. Inhibition of NF-kB activity prevented Gata-3 expression, LC3 positive autophagosomes and Th2 cytokine production in BLOC1S1 −/− CD4 +T cells. This mouse model will now give us a platform to explore the role of endo-lysosomal biology in Th2 polarization and activation. NHLBI Division of Intramural Research (MNS-ZIA-HL005102)