Our laboratory is investigating the roles played by γδ T cells during infection and tissue repair. We are interested in understanding how γδ T cells have the capacity to recognize and destroy virus-infected cells, but are also able to produce growth factors and heal tissue. We are currently uncovering the mechanisms required for these diverse functions.

Role of mTOR in skin γδ T cell tissue repair

Rapamycin is an immunosuppressant currently approved for use in kidney transplant recipients for the prophylaxis of acute rejection and for use on arterial stents. An unfortunate side effect of the drug is impaired wound healing. We have shown that rapamycin inhibits skin γδ T cell motility, proliferation, and IGF-1 production (Mills et al., J. Immunol, 2008). We have observed defects in wound closure that is rescued by the addition of soluble factors such as KGF-1 or IGF-1, suggesting that restoring skin γδ T cell function may increase the efficiency of wound repair. Rapamycin targets the serine kinase mTOR, which is thought to be a scaffold protein that pulls together proteins to target downstream effectors such as S6Kinase for cell cycle regulation. We are now further elucidating the role of mTOR in skin γδ T cell function during homeostasis and wound repair.

Human resident T cells in wound repair

Little is known about the function of skin resident T cells in humans. There are not only γδ T cells, but also αβ T cells that reside in the epidermis and the dermis of humans.We have determined that skin T cells in the human have the capacity to produce growth factors during wound repair (Toulon, et al., J. Exp. Med. 2009). Now we are examining whether T cells migrate to the wound site and what roles they may play there. Studies to examine the role of mTOR in skin T cell function in humans are also underway.

Function of skin γδ T cells in obesity and metabolic disease

Diabetic patients have an increased risk of wound healing complications with 5-10% of diabetic patients suffering from chronic nonhealing ulcers. It has been reported that levels of KGFs and IGF-1 in diabetic human and murine wounds are decreased. We have recently shown that skin γδ T cells lose the ability to proliferate homeostatically in mouse models of obesity and metabolic disease (Taylor et al, PLoS One, 2010). In addition, our studies have identified a defect in skin γδ T cell wound healing functions in obese and diabetic mice, suggesting that restoring normal T cell function may improve the course of healing. We are currently examining skin from obese and diabetic patients to identify if a similar inhibition occurs in humans.

Peripheral blood γδ T cell responses to influenza in humans

Influenza A virus epidemics and pandemics can have devastating consequences, therefore the development of a vaccine that can provide subtype and strain cross-reactive protection is being heavily investigated. We have recently identified a population of γδ T cells in the peripheral blood of humans that rapidly recognizes influenza virus infected cells and produces the anti-viral cytokine IFN-γ (Jameson et al., Cell. Immunol. 2010). Activation and recognition of the infected cells requires the mevalonate pathway suggesting that the response is directed at isopentenyl pyrophosphate (IPP), a metabolite in the mevalonate pathway previously shown to activate γδ T cells in the PBMC. Now we are determining whether the recognition is specific to IPP, how the virus impairs this pathway, and whether γδ T cell responses reduce viral replication.