Adipocyte CD1d Gene Transfer Induces T Cell Expansion and Adipocyte Inflammation in CD1d Knockout Mice

Abstract

CD1d, a lipid Ag-presenting molecule for invariant NKT (iNKT) cells, is abundantly expressed on adipocytes and regulates adipose homeostasis through iNKT cells. CD1d gene expression was restored in visceral adipose tissue adipocytes of CD1d knockout (KO) mice to investigate the interactions between adipocytes and immune cells within adipose tissue. We developed an adipocyte-specific targeting recombinant adeno-associated viral vector, with minimal off-target transgene expression in the liver, to rescue CD1d gene expression in visceral adipose tissue adipocytes of CD1d KO mice, followed by assessment of immune cell alternations in adipose tissue and elucidation of the underlying mechanisms of alteration. We report that adeno-associated virusmediated gene transfer of CD1d to adipocytes in CD1d KO mice fails to rescue iNKT cells but leads to massive and selective expansion of T cells within adipose tissue, particularly CD8 + T effector cells, that is associated with adipocyte NLRP3 inflammasome activation, dysregulation of adipocyte functional genes, and upregulation of apoptotic pathway proteins. An NLRP3 inhibitor has no effect on T cell phenotypes whereas depletion of CD8 + T cells significantly attenuates inflammasome activation and abolishes the dysregulation of adipocyte functional genes induced by adipocyte CD1d. In contrast, adipocyte overexpression of CD1d fails to induce T cell activation in wild-type mice or in invariant TCR a-chain Ja18 KO mice that have a normal lymphocyte repertoire except for iNKT cells. Our studies uncover an adipocyte CD1d fi CD8 + T cell fi adipocyte inflammasome cascade, in which CD8 + T cells function as a key mediator of adipocyte inflammation likely induced by an allogeneic response against the CD1d molecule.

Contribution of NKT cells and CD1d-expressing cells in obesity-associated adipose tissue inflammation

“…re-expressed CD1d by transferring the Cd1d gene into the visceral AT (VAT) of CD1d KO mice using an adeno-associated viral (AAV) vector to investigate the interactions between adipocytes and immune cells. The mice with the Cd1d gene transferred showed massive expansion of CD8 + T cells in the VAT, leading to the dysregulation of adipocyte functions through the activation of the NLRP3 inflammasome ( 77 ). Although the transduced mice exhibited a 25% reduction in VAT weight, there was no significant change in other parts of the AT.…”