Commensal bacteria negatively regulate skin inflammation by inhibiting proliferation of CD8+ Tissue resident memory T cells

Summary: Abstract Body: This study explored how commensal bacteria regulate CD8+ Tissue-resident memory T cells (Trm) and their role in skin inflammation. Autoimmune and inflammatory skin disorders have complex, immune-mediated pathophysiology, often prone to relapse after drug withdrawal. Trm play a critical role in these relapses. Commensal bacteria on lesional skin differ significantly from those on healthy skin, influencing immune homeostasis. However, the relationship between commensal bacteria and Trm, and their role in skin inflammation, remains unclear. Using a DNFB-induced skin inflammation model in specific pathogen-free (SPF), germ-free (GF), and SPF mice treated with Staphylococcus epidermidis, we analyzed CD8+ Trm numbers, distribution, and cytokine secretion. Metabolomics and RNA sequencing investigated potential mechanisms. Skin commensal bacteria alleviated recurrent skin inflammation, reducing ear thickness (p<0.0001), epidermal thickening, and dermal edema in Staphylococcus epidermidis-treated mice (p<0.0001). Flow cytometry revealed decreased CD8+ Trm infiltration in lesional skin (p=0.0097). Staphylococcus epidermidis inhibited CD8+ Trm accumulation 30 days post-DNFB stimulation, lowering their percentage and count (p=0.0052). Bacterial metabolites had similar effects, with metabolomics identifying key substances. Additionally, Staphylococcus epidermidis reduced CD8+ Trm IFN-γ secretion (p=0.0439) and proliferative capacity (p=0.0286), impairing their function and persistence. RNA-seq of CD8+ Trm and scRNA-seq of immune cells showed significant downregulation of the PPAR signaling pathway, glutathione metabolism, and fatty acid degradation pathway 3 days post-Staphylococcus epidermidis treatment. This study demonstrates that skin commensal bacteria, particularly through organic acid metabolites, regulate CD8+ Trm persistence in skin inflammation. These findings suggest the therapeutic potential of bacterial metabolites in treating inflammatory skin diseases. Nan Yang^{1, 2}, Zeyu Chen^{1, 2}, Yuling Shi^{1, 2} 1. Department of Dermatology, Shanghai Skin Diseases Hospital, Shanghai, Shanghai, China. 2. Institution of Psoriais, Tongji University School of Medicine, Shanghai, Shanghai, China. Innate Immunity, Microbiology, and Microbiome