The Role of Gamma Delta T Cells in Adipose Tissue Biology

Abstract

Adipose tissue harbors a unique and diverse immune compartment that is important for physiologic responses to fasting and feeding and regulation of body weight and thermogenesis. Compared to lymphoid organs, adipose tissue is enriched for resident innate leukocytes where approximately 80-90% of the immune system is considered innate. Much of what we know about the adipose immune system suggests its major roles are not focused on fighting infection. Instead, obesity studies reveal that perturbations in immune cells or signaling molecules can either protect or contribute to inflammation and subsequent insulin resistance. Although not well understood, it is likely that the resident innate immune compartment within the adipose tissue may also have important functions at steady state. γδ T cells are guardians at barrier sites and rapidly respond to the presence of cellular stress and foreign pathogens. Subsequently, γδ T cells can exert a wide range of functions to initiate the appropriate response to protect the host. However, little is known about their steady state role in non-barrier tissues. Here, we characterize a highly enriched, resident population of γδ T cells in adipose tissue that regulates age-dependent adipose T regulatory cell expansion and controls core body temperature in response to environmental fluctuations. These adipose γδ T cells express and rely on the transcription factor PLZF and transcriptional profiling of PLZF+ γδ T cells reveals their innate-phenotype and functional capacity to produce TNF and IL-17A. Using a combination of tissue immune-phenotyping and in vitro co-culture assays, we have identified a mechanism by which innate PLZF+ γδ T cells cross talk with adipose stromal cells and regulate endogenous IL-33 levels to maintain adipose T regulatory homeostasis. Surprisingly, mice deficient in γδ T cells also lack the ability to regulate core body temperature at thermoneutrality and after cold challenge due to their inability to support non-shivering thermogenesis. Our work opens a new dimension in adipose biology, where dynamic communication between resident innate lymphocytes and stromal cells can dictate tissue homeostasis. Additionally, our findings uncover important physiological roles for γδ T cells in adipose T regulatory cell maintenance and regulation of systemic energy expenditure.