Induction of adipose-resident NKT cells can be instructed by non ligand-binding motifs of the TCR β chain.

Abstract

Abstract Invariant Natural Killer T (NKT) cells, a CD1d-restricted subset of αβ T cells, have been increasingly recognized for their role in a wide variety of functions associated with autoimmunity, cancer, infection, tolerance, and obesity. The semi-invariant TCR expressed by NKT cells is unique in its recognition of glycolipids presented by CD1d, heterodimer rigidity, and limited binding footprint compared to conventional TCR:MHC interactions. This distinctive interaction has been studied extensively in vitro, though the role of the rigid α:β heterodimer in the selection and development of NKT cells remains elusive. We investigated a hydrophobic patch on the β chain of the NKT TCR, suggested to play a role in heterodimer stability. Partial disruption of this patch, while permissive of ligand binding, resulted in decreased populations of NKT cells, diminished development, and effector function. Complete disruption of the patch resulted in the ablation of the NKT cell compartment entirely, while still accommodating conventional T cell development. NKT cells expressing the mutant NKT TCR acquired an adipose-resident NKT phenotype while in the thymus, and accumulated in the adipose tissue in mice. Hence, we show that in vivo, non-ligand binding regions of the NKT TCR are critical for the development of these important immune cells, and mediate the selection of adipose-resident NKT cells.