iNKT cells are now recognized as powerful cytokine producing cells that are activated by either self or foreign lipid antigens presented by CD1d (signal 1) in combination with cytokine driven second signals. The structure of the lipid antigens, nature of the APC and type of cytokine are all peripheral cues that influence the effector cytokines they produce. iNKT cells may take on Th1-like, Th2-like and Th17-like responses determined both by their thymic differentiation and by the peripheral signals they encounter during activation. Their development in the thymus is dependent on the up-regulation of the transcription factor, PLZF, considered a 'master regulator'of the lineage. This transcription factor is responsible for expression of the effector/memory phenotype that enables iNKT cells to be 'poised'for rapid secretion of effector cytokines, without requiring priming. Recognition by th semi-invariant TCR enables much of the population to respond, all at once, to the same antigen. Thus, iNKT cells are considered 'innate'T cells. Here, we propose to characterize a newly identified subset of iNKT cells that is remarkably different from those described before. iNKT cells localized in adipose tissue do not display the Th-1, Th-2 or Th-17 phenotype of other iNKT cells, but instead primarily produce IL-10 and IL-2. They regulate inflammation in adipose tissue by driving macrophages to the M2 phenotype via IL-10 and by regulating the number and the function of Tregs in adipose tissue via secretion of IL-2. Their unusual cytokine skewing is part of a larger underlying program that we found to be characterized by the lack of expression of PLZF and up-regulation of the transcription factor E4BP4. We show that E4BP4 drives their IL-10 secretion and down-regulates PLZF expression.
In Aim 1, we will define the molecular mechanism by which E4BP4, a negative regulator of transcription, controls PLZF expression by determining if it binds to the PLZF promotor or induces chromatin changes influencing the PLZF locus. We also show that exposure of non-adipose iNKT cells to adipose tissue activates them via TCR recognition, up-regulates E4BP4 and turns on a new underlying transcriptional program. We show that adipose tissue lipid antigen extracts and adipose tissue-derived soluble factors both activate iNKT cells. Thus, we propose to purify and identify the lipid antigens in adipose tissue that activate iNKT cells (Aim 2) and identify the soluble factors from adipose tissue that activate iNKT cells (Aim 3) and combine these adipose-derived activation cues with CD1d expressing adipose APCs to reconstitute adipose-driven iNKT cell activation and skewing in vitro. Together, these aims will define the environmental (adipose tissue-selective) activation cues and transcriptional program that drives a new innate """"""""regulatory"""""""" iNKT cell subset with important implications for adipose tissue inflammation, obesity, and type II diabetes.

Public Health Relevance

We have found a unique subset of white blood cells that instead of causing inflammation suppress inflammation. They are found in fat tissue, and they are activated by factors made by fat tissue. When activated these special cells protect fat tissue from too much inflammation. Obesity and diabetes, in part, are caused by inflammation in fat tissue. Thus, these special white blood cells may be important in preventing obesity and diabetes. Furthermore, if drugs can be developed that activate them, they would provide new approaches to treating these diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Innate Immunity and Inflammation Study Section (III)
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Miller, Lara R
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Brigham and Women's Hospital
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LaMarche, Nelson M; Kohlgruber, Ayano C; Brenner, Michael B (2018) Innate T Cells Govern Adipose Tissue Biology. J Immunol 201:1827-1834
Chang, Sook Kyung; Kohlgruber, Ayano C; Mizoguchi, Fumitaka et al. (2017) Stromal cell cadherin-11 regulates adipose tissue inflammation and diabetes. J Clin Invest 127:3300-3312
Brennan, Patrick J; Cheng, Tan-Yun; Pellicci, Daniel G et al. (2017) Structural determination of lipid antigens captured at the CD1d-T-cell receptor interface. Proc Natl Acad Sci U S A 114:8348-8353
Kohlgruber, Ayano C; Donado, Carlos A; LaMarche, Nelson M et al. (2016) Activation strategies for invariant natural killer T cells. Immunogenetics 68:649-63
Lynch, Lydia; Hogan, Andrew E; Duquette, Danielle et al. (2016) iNKT Cells Induce FGF21 for Thermogenesis and Are Required for Maximal Weight Loss in GLP1 Therapy. Cell Metab 24:510-519
Lynch, Lydia; Michelet, Xavier; Zhang, Sai et al. (2015) Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of T(reg) cells and macrophages in adipose tissue. Nat Immunol 16:85-95