Altered human γδ peripheral blood lymphocyte homeostasis and impaired influenza A viral response in obesity (168.9)

Abstract

Abstract Obesity is an independent risk factor for severe and fatal influenza infection. Little is known about how obesity impacts influenza-specific T cell responses in humans. In healthy adults, γδ T cells are the major circulating population of T cells that rapidly respond to influenza virus infected APCs. The majority express a Vγ9Vδ2 TCR that recognizes phosphoantigens expressed by infected or transformed cells. To determine whether this anti-viral T cell population was impacted by obesity, human peripheral blood mononuclear cells were isolated from non-obese and obese donors and analyzed for homeostatic T cell numbers and function. We found the percentage of Vγ9Vδ2 T cells negatively correlates with increased body mass index (BMI), suggesting the severity of obesity impacts γδ T cell homeostasis. Furthermore, Vγ9Vδ2 T cells exhibit a skewed maturation, with a higher propensity toward a unique γδ T effector CD45RA+ memory cell population. We have identified that obese patients show reduced expression of the homing molecule CCR5 on γδ T cells as well as reduced IFN-γ and TNF-α production in response to influenza infection. This blunted Vγ9Vδ2 T cell response in obese patients is T cell intrinsic as function can be rescued using a strong TCR agonist. Our data show that one arm of the antiviral immune response to influenza is compromised by obesity. These studies support the concept that therapies should be developed to restore immune homeostasis in obese patients.