Autism-related CHD8 is required for maintaining Treg cell fitness

---

Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B734
Abstract ID: 5681

Presenting Author:
Junqi Yang , Research Associate at Cincinnati Children’s Hosp. Med. Ctr., Univ. of Cincinnati Col. of Med.

Abstract:

CHD8 is an adenosine triphosphate (ATP)-dependent chromatin remodeler, the mutations of which define a subtype of autism spectrum disorders. CHD8 has recently been found to be important for hematopoietic stem cell survival and erythroblast cytokinesis. It remains unclear whether CHD8 plays a role in regulatory T (Treg) cells that suppress effector T cells such as CD4⁺ Th1/Th2/Th17 cells and CD8⁺ cytotoxic T cells to maintain immune tolerance.  In this study we have generated Treg cell-specific CHD8-deficient mice. We found that CHD8 deletion led to early, fatal systemic inflammatory disorders. The autoimmune responses came from an increase in activated CD4⁺ and CD8⁺ T cells and in effector T cells including Th1, Th2 and Th17 cells. The immune activation was due to increased Treg cell plasticity as evidenced by increased effector T cell cytokine expression in Treg cells. Paradoxically, CHD8 deletion upregulated Treg cell functional markers such as CTLA-4, PD-1, GITR and ICOS, indicative of functional exhaustion. RNA-seq revealed that CHD8 deletion upregulated a number of hallmark pathways including inflammatory response, p53 pathway, apoptosis, G2M checkpoint, mTORC1 signaling, glycolysis, oxidative phosphorylation, and reactive oxygen species pathway. Collectively, our findings suggest that CHD8 is required for maintaining Treg cell fitness and function by modulating p53-mediated cell survival and cell cycle progression, and mTOR-mediated mitochondrial metabolism.