γδ T cells promote inflammation and insulin resistance during high fat diet-induced obesity in mice

gamma delta T cells are resident in AT and increase during diet-induced obesity. Their possible contribution to the inflammatory response that accompanies diet-induced obesity was investigated in mice after a 5 to 10 week milk HFD. The HFD resulted in significant increases in CD44(hi), CD62L(lo), and TNF-alpha(+) gamma delta T cells in eAT of WT mice. Mice deficient in all gamma delta T cells (TCR delta(-/-)) or only V gamma 4 and V gamma 6 subsets (V gamma 4/6(-/-)) were compared with WT mice with regard to proinflammatory cytokine production and macrophage accumulation in eAT. Obesity among these mouse strains did not differ, but obese TCR delta(-/-) and V gamma 4/6(-/-) mice had significantly reduced eAT expression of F4/80, a macrophage marker, and inflammatory mediators CCL2 and IL-6 compared with WT mice. Obese TCR delta(-/-) mice had significantly reduced CD11c(+) and TNF-alpha(+) macrophage accumulation in eAT after 5 and 10 weeks on the HFD, and obese V gamma 4/6(-/-) mice had significantly increased CD206(+) macrophages in eAT after 5 weeks on the diet and significantly reduced macrophages after 10 weeks. Obese TCR delta(-/-) mice had significant reductions in systemic insulin resistance and inflammation in liver and skeletal muscle after longer-term HFD feeding (10 and 24 weeks). In vitro studies revealed that isolated gamma delta T cells directly stimulated RAW264.7 macrophage TNF-alpha expression but did not stimulate inflammatory mediator expression in 3T3-L1 adipocytes. These findings are consistent with a role for gamma delta T cells in the proinflammatory response that accompanies diet-induced obesity.