BLOC1S1 control of vacuolar organelle homeostasis modulates Th2 immune responsiveness and allergy susceptibility

The levels of biogenesis of lysosome organelles complex 1 subunit 1 (BLOC1S1) control mitochondrial and endolysosome organelle homeostasis and function. Reduced fidelity of these vacuolar organelles is increasingly being recognized as influential in instigating cell-autonomous immune cell activation. We reasoned that exploring the role of BLOC1S1 in CD4+ T cells may further advance our understanding of regulatory events linked to mitochondrial and endolysosomal function in adaptive immunity.

We report that BLOC1S1-/- CD4+ T cells from mice and humans show enhanced Th2 activation. Transcript levels of the canonical transcription factors driving CD4+ T cell showed that the Th2 regulator GATA3 was exclusively induced in BLOC1S1-/- CD4+ cells. In parallel, in response to both T cell receptor activation and to Th2 polarization, the levels of IL-4, IL-5 and IL-13 were markedly induced in the absence of BLOC1S1. At a functional level, BLOC1S1-/- mice displayed increased susceptibility to allergic conditions, including atopic dermatitis and asthma. At the organelle level, mitochondrial DNA leakage is evident with STING accumulation on lysosomes and activation of the cGAS-STING NF-kB pathway to drive Th2 polarization. The genetic knockdown of STING in cultured CD4+ T cells ameliorates this immune regulatory cascade. In conclusion, we provide the first evidence that BLOC1S1 is essential in regulating Th2 cell expansion and developing type 2 allergic responses.