BLOC1S1 Control of Vacuolar Organelle Fidelity Modulates Murine T_H2 Cell Immunity and Allergy Susceptibility

Background: 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 important 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/or endolysosomal function in adaptive immunity.

Methods: CD4⁺ T cells were analyzed from control and CD4⁺ T-cell-specific BLOC1S1 knockout mice. Polarization profiles were assayed using biochemical and molecular signatures, and signaling pathways were disrupted pharmacologically or via siRNA. Mouse models of airway and skin inflammation were generated by Ovalbumin and MC903 exposure, respectively.

Results: T_H2 regulator GATA3 and phosphorylated STAT6 were preferentially induced in BLOC1S1-depleted primary CD4⁺ T (TKO) cells. The levels of IL-4, IL-5, and IL-13 were markedly induced in the absence of BLOC1S1. At the organelle level, mitochondrial DNA leakage evoked cGAS-STING and NF-κB pathway activation with subsequent T_H2 polarization. The induction of autophagy with rapamycin reduced cytosolic mtDNA and reversed these T_H2 signatures. Furthermore, genetic knockdown of STING and NF-κB inhibition ameliorated this immune regulatory cascade in TKO cells. Finally, at a functional level, TKO mice displayed an increased susceptibility to allergic conditions, including dermatitis and allergic asthma.

Conclusions: BLOC1S1 depletion in mouse CD4⁺ T cells mediated disruption of mitochondrial integrity to initiate a predominant T_H2-responsive phenotype via STING-NF-κB-driven signaling of the canonical T_H2 regulatory program.