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Title: Gamma delta T cells promote inflammation and insulin resistance during high fat diet-induced obesity in mice

Author
item MEHTA, POOJA - Baylor College Of Medicine
item NUOTIO-ANTAR, ALLI - Baylor College Of Medicine
item SMITH, C. WAYNE - Children'S Nutrition Research Center (CNRC)

Submitted to: Journal of Leukocyte Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/31/2014
Publication Date: 1/1/2015
Citation: Mehta, P., Nuotio-Antar, A.M., Smith, C. 2015. Gamma delta T cells promote inflammation and insulin resistance during high fat diet-induced obesity in mice. Journal of Leukocyte Biology. 97:121-134.

Interpretive Summary: Mice fed a high fat diet develop obesity and inflammation in body tissues such as the fat pads in the abdomen, skeletal muscles and liver. This study investigated the contribution of a specific class of white blood cells called gamma delta T cells to the inflammation in the fat pads, skeletal muscle and liver. The results revealed that mice genetically engineered to have no gamma T cells had significantly less inflammation in these tissues when fed a high fat diet for up to 20 weeks, even though these mice developed obesity to the same extent as control mice with normal numbers of gamma delta T cells. These results indicate that this class of white blood cells is an important contributor to high fat diet-induced inflammation, but plays no apparent role in the development of obesity.

Technical Abstract: Gamma delta T cells are resident in adipose tissue and increase during diet-induced obesity. Their possible contribution to the inflammatory response that accompanies diet-induced obesity was investigated in mice after a 5-10 week high milk fat diet. The high milk fat diet resulted in significant increases in CD44hi CD62Llo TNF-alpha + gamma delta T cells in epididymal AT of wildtype mice. Mice deficient in all gamma delta T cells (TCRd-/-) or only V gamma 4 and V gamma 6 subsets (V gamma 4/6-/-) were compared with wildtype mice with regard to pro-inflammatory cytokine production and macrophage accumulation in adipose tissue. Obesity among these mouse strains did not differ, but obese TCRd-/- and V gamma 4/6-/- mice had significantly reduced epididymal AT expression of F4/80, a macrophage marker, and inflammatory mediators CCL2 and IL-6 compared to wildtype mice. Obese TCRd-/- mice had significantly reduced CD11c+ and TNF-alpha+ macrophage accumulation in epididymal AT after 5 and 10 weeks on the high milk fat diet, and obese V gamma 4/6-/- mice had significantly increased CD206+ macrophages in epididymal AT after 5 weeks on the diet and significantly reduced macrophages after 10 weeks. Obese TCRd-/- mice had significant reductions in systemic insulin resistance and inflammation in liver and skeletal muscle after longer-term high milk fat diet feeding (10 weeks and 6 months). In vitro studies revealed that isolated gamma delta T cells directly stimulated RAW264.7 macrophage TNF-alphs 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 pro-inflammatory response that accompanies diet-induced obesity.