Obesity impairs γδ T cell homeostasis and antiviral function in humans.

Obese patients are susceptible to increased morbidity and mortality associated with infectious diseases such as influenza A virus. γδ T cells and memory αß T cells play key roles in reducing viral load by rapidly producing IFN-γ and lysing infected cells. In this article we analyze the impact of obesity on T lymphocyte antiviral immunity. Obese donors exhibit a reduction in γδ T cells in the peripheral blood. The severity of obesity negatively correlates with the number of γδ T cells. The remaining γδ T cells have a skewed maturation similar to that observed in aged populations. This skewed γδ T cell population exhibits a blunted antiviral IFN-γ response. Full γδ T cell function can be restored by potent stimulation with 1-Hydroxy-2-methyl-buten-4yl 4-diphosphate (HDMAPP), suggesting that γδ T cells retain the ability to produce IFN-γ. Additionally, γδ T cells from obese donors have reduced levels of IL-2Rα. IL-2 is able to restore γδ T cell antiviral cytokine production, which suggests that γδ T cells lack key T cell specific growth factor signals. These studies make the novel finding that the γδ T cell antiviral immune response to influenza is compromised by obesity. This has important implications for the development of therapeutic strategies to improve vaccination and antiviral responses in obese patients.

Dysfunctional γδ T cells contribute to impaired keratinocyte homeostasis in mouse models of obesity.

Skin complications and chronic non-healing wounds are common in obesity, metabolic disease, and type 2 diabetes. Epidermal γδ T cells normally produce keratinocyte growth factors, participate in wound repair, and are necessary for keratinocyte homeostasis. We have determined that in γδ T cell-deficient mice, there are reduced numbers of keratinocytes and the epidermis exhibits a flattened, thinner structure with fewer basal keratinocytes. This is important in obesity, where skin-resident γδ T cells are reduced and rendered dysfunctional. Similar to γδ T cell-deficient mice, keratinocytes are reduced and the epidermal structure is altered in two obese mouse models. Even in regions where γδ T cells are present, there are fewer keratinocytes in obese mice, indicating that dysfunctional γδ T cells are unable to regulate keratinocyte homeostasis. The impact of absent or impaired γδ T cells on epidermal structure is exacerbated in obesity as E-cadherin localization and expression are additionally altered. These studies reveal that γδ T cells are unable to regulate keratinocyte homeostasis in obesity and that the obese environment further impairs skin structure by altering cell-cell adhesion. Together, impaired keratinocyte homeostasis and epidermal barrier function through direct and indirect mechanisms result in susceptibility to skin complications, chronic wounds, and infection.

Gammadelta T cells are reduced and rendered unresponsive by hyperglycemia and chronic TNFalpha 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 gammadelta T cells recognize epithelial damage, and release cytokines and growth factors that facilitate wound repair. We report here that hyperglycemia results in impaired skin gammadelta T cell proliferation due to altered STAT5 signaling, ultimately resulting in half the number of gammadelta T cells populating the epidermis. Skin gammadelta T cells that overcome this hyperglycemic state are unresponsive to epithelial cell damage due to chronic inflammatory mediators, including TNFalpha. Cytokine and growth factor production at the site of tissue damage was partially restored by administering neutralizing TNFalpha antibodies in vivo. Thus, metabolic disease negatively impacts homeostasis and functionality of skin gammadelta T cells, rendering host defense mechanisms vulnerable to injury and infection.