Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Mitochondrial fidelity

• BLOC1S1

• TH2 immunity

• STING signalling

Main Findings

Mitochondria regulate various cellular processes such as energy metabolism, signalling, and differentiation. Their dysfunction is linked to the development of various diseases. In this study, the authors investigated the role of biogenesis of lysosome organelles complex 1 subunit 1 (BLOC1S1) in CD4+ T cell biology. Previous studies have shown that BLOC1S1 modulates the integrity and function of mitochondria and endolysosomes. Using mice with a T cell-specific knockout of BLOC1S1, the authors performed a series of in vitro and in vivoexperiments to dissect the function of BLOC1S1 in the differentiation and effector of CD4+ T cells.

The loss of Bloc1s1 led to enhanced expression of the Th2 cytokines interleukin (IL)-4, IL-5, and IL-13 as well as GATA3 in activated CD4+ T cells. However, the deletion of BLOC1S1 did not affect the expression of T-bet, RORgt, and FoxP3, the lineage-determining transcription factors for Th1, Th17 and Treg cells, respectively. Interestingly, the loss of BLOC1S1 in human CD4+ T cells also potentiated the expression of Th2 cytokines and GATA3. Given the impact of BLOC1S1 deletion on the expression of Th2 cytokines in both mouse and human CD4+ T cells, the study focused on dissecting the mechanisms of BLOC1S1-mediated regulation of Th2 cell biology.

Since previous studies have shown that BLOC1S1 is essential in maintaining mitochondrial integrity and that the release of mitochondrial DNA (mtDNA) following perturbation activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, the authors examined this axis as a potential mechanism driving the induction of Th2 cytokines in absence of BLOC1S1. Indeed, BLOC1S1-deficient CD4+T cells showed increased levels of cytosolic mtDNA coupled with enhanced expression and phosphorylation of cGAS and STING. Interestingly, pharmacological inhibition or knockdown of STING suppressed NF-kB activation and Th2 cytokine expression, particularly in BLOC1S1-deficient CD4+ T cells. These results highlight that the STING-NF-kB axis drives the upregulation of Th2 cytokines in BLOC1S1-deficient CD4+ T cells. Finally, the authors demonstrated that BLOC1S1 is essential to limit both calcipotriol-induced atopic dermatitis and ovalbumin-induced airway inflammation, two Th2-driven pathologies. Taken together, this study pinpoints BLOC1S1 as a novel regulator of Th2 cell biology and a potential therapeutic target in Th2-mediated diseases.

Limitations

• The materials and methods section of the manuscript should be described in more detail. It is sometimes unclear whether the authors used total or just naïve CD4+ T cells. The catalogue numbers for some of the materials used should be provided for reproducibility.

• Since the manuscript focuses on Th2 cell biology, in vitro-generated Th2 cells should also be used to study the impact of BLOC1S1 deletion and not just Th0 cells.

• A detailed transcriptome profiling will shed more light on the mechanism(s) promoting type 2 cytokine secretion in BLOC1S1-deficient CD4+ T cells.

• It will be interesting to measure the level of cyclic AMP-GMP in the cells since it activates STING signalling.

• Quantification of histology data in both allergy models will be helpful for the interpretation of the results.

• The authors should consider characterisation of immune cell infiltration in the skin and lungs.

• Since STING inhibition reverses the impact of BLOC1S1 deletion in vitro, it will be useful to also test this in vivo using their allergy models.

• Although the authors indicated in the materials and methods that human CD4+ T cells were treated with NF-kB and STING inhibitors, these data are missing.

Significance/Novelty

Mechanisms and impact of mitochondrial dysfunction in CD4+ T cells are incompletely understood. This study reveals for the first time that BLOC1S1 maintains CD4+ T cell mitochondrial integrity to restrict Th2 cytokine production and allergic diseases.

Given the important role of Th2 cells in various diseases including allergies, a deeper understanding of their biology is of utmost importance.

Credit

Reviewed by Matarr Khan as part of a cross-institutional journal club between the Vanderbilt University Medical Center(VUMC), the Max-Delbrück Center Berlin, the Ragon Institute Boston (Mass General, MIT, Harvard), the Medical University of Vienna and other life science institutes in Vienna.

The author declares no conflict of interests in relation to their involvement in the review