Obesity enhances antiviral immunity in the genital mucosa through a microbiota-mediated effect on γδ T cells

Obesity is detrimental to the immune system. It impairs lymphatics, T cell development, and lymphopoiesis; induces dysfunction of antitumor immunity; and also promotes tumor progression. However, direct evidence of the impact of obesity on viral infection is lacking. We found an unexpected protective role of obesity against herpes simplex virus 2 infection of the genital mucosa in mice. Although conventional antiviral immunity was comparable between obese mice and lean mice, obesity enhanced the cytotoxic subset of γδ T cells. This effect was mediated by L-arginine produced by commensal microbiota in the genital mucosa, which induced “pseudonormoxia” of γδ T cells, resulting in increased NKG2D expression of γδ T cells through the downregulation of HIF1A by inducing NO production, thereby protecting mice from lethal genital herpes. Thus, our work illuminates one mechanism by which obesity-induced compositional changes in the vaginal microbiota can affect mucosal immune responses against viral infection. 5 wks-old female C57BL/6J mice were fed with SCD or 60%kcal HFD for 10 weeks. MPA was subcutaneously injected to the mice at the 9 weeks of feeding. At 10 weeks of feeding, mice were infected with 10^4 pfu of HSV-2 WT intravaginally. At 0 or 3 days post infection, vagina were harvested and single cell suspensions were isolated. 10 0 dpi mice were pulled for one sample and 5 3 dpi mice were pulled for one sample. By FACS Aria II, 7-AAD- live cells were sorted. 10,000 cells per sample were sequenced.