NKT TCR domains unrelated to ligand binding instruct the thymic development of an adipose resident subset — ASN Events
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  3. NKT TCR domains unrelated to ligand binding instruct the thymic development of an adipose resident subset

NKT TCR domains unrelated to ligand binding instruct the thymic development of an adipose resident subset (#150)

Joshua A Vieth 1 2 , Joy Das 3 , Fanomezana M Ranaivoson 1 2 , Davide Comoletti 1 2 4 , Lisa K Denzin 1 2 5 6 7 , Derek B Sant'Angelo 1 2 5 6 7
  1. The Child Health Institute of NJ, Rutgers University, New Brunswick, NJ, USA
  2. Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
  3. Immunology Program, Sloan Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
  4. Department of Neuroscience and Cell Biology, Rutgers University, New Brunswick, NJ, USA
  5. Rutgers Graduate School of Biomedical Sciences, Rutgers University, New Brunswick, NJ, USA
  6. Department of Pediatrics, Rutgers University, New Brunswick, NJ, USA
  7. Department of Pharmacology, Rutgers University, New Brunswick, NJ, USA

The role of natural killer T cells (NKT cells) in adipose tissue is a topic of much interest, as reports have suggested a correlation between depletion of the adipose-resident NKT (arNKT) cell population and chronic obesity. It has been shown that arNKT cells are unique in terms of their function and phenotype; they produce anti-inflammatory and regulatory cytokines, and also induce the accumulation of FoxP3-expressing Tregs in adipose tissue. There has been much speculation about whether these arNKT cells are a unique subset of the NKT cell repertoire or whether NKT cells take on a regulatory phenotype due to external cues in the adipose microenvironment. Our recently published work focused on the uniquely conserved NKT T cell antigen receptor (TCR) and the role its seemingly rigid structure plays in the selection and development of NKT cells. In fact, the interaction between the NKT TCR and the antigen-presenting molecule CD1d is distinct from interactions between the TCR and major histocompatibility complex (MHC) in many ways, including decreased total buried surface area, less post-ligation conformational changes, and yet increased overall avidity. Our molecular modeling suggested that a hydrophobic patch created after TCRα –TCRβ pairing has a role in maintaining the conformation of
the NKT cell TCR. Disruption of this patch ablated recognition of CD1d by the NKT cell TCR but not interactions of the TCR with MHC. Partial disruption of the patch, while permissive to the recognition of CD1d, significantly altered NKT cell development, which resulted in the selective accumulation of adipose-tissue-resident NKT cells. These results indicate that a key component of the TCR is essential for the development of a distinct population of NKT cells, and provide the first data evidencing that arNKT cells are a distinct lineage of NKT cells that develop in the thymus.