γδ T Cells Are Reduced and Rendered Unresponsive by Hyperglycemia and Chronic TNFα in Mouse Models of Obesity and Metabolic Disease

Epithelial cells provide an initial line of defense against damage and pathogens in barrier tissues such as the skin; however this balance is disrupted in obesity and metabolic disease. Skin gamma delta T cells recognize epithelial damage, and release cytokines and growth factors that facilitate wound repair. We report here that hyperglycemia results in impaired skin gamma delta T cell proliferation due to altered STAT5 signaling, ultimately resulting in half the number of gamma delta T cells populating the epidermis. Skin gamma delta T cells that overcome this hyperglycemic state are unresponsive to epithelial cell damage due to chronic inflammatory mediators, including TNF alpha. Cytokine and growth factor production at the site of tissue damage was partially restored by administering neutralizing TNF alpha antibodies in vivo. Thus, metabolic disease negatively impacts homeostasis and functionality of skin gamma delta T cells, rendering host defense mechanisms vulnerable to injury and infection.