Abstract
Invariant natural killer T cells (iNKTs) are innate-like T cells that are highly concentrated in the liver and recognize lipids presented on the MHC-like molecule CD1d. Although capable of a myriad of responses, few essential functions have been described for iNKTs. Among the many cell types of the immune system implicated in metabolic control and disease, iNKTs seem ideally poised for such a role, yet little has been done to elucidate such a possible function. We hypothesized that lipid presentation by CD1d could report on metabolic status and engage iNKTs to regulate cellular lipid content through their various effector mechanisms. To test this hypothesis, we examined CD1d deficient mice in a variety of metabolically stressed paradigms including high fat feeding, choline-deficient feeding, fasting, and acute inflammation. CD1d deficiency led to a mild exacerbation of steatosis during high fat or choline-deficient feeding, accompanied by impaired hepatic glucose tolerance. Surprisingly, however, this phenotype was not observed in Jα18−/− mice, which are deficient in iNKTs but express CD1d. Thus, CD1d appears to modulate some metabolic functions through an iNKT-independent mechanism.
Highlights
In recent years, it has become increasingly clear that molecules and cells classically associated with the immune system have important roles in maintenance of whole body energy metabolism
Results Invariant natural killer T cells (iNKTs) are selectively decreased in obese livers Consistent with previous reports [19,20,21,32], we found that high fat feeding led to a significant reduction of PBS57-CD1d tetramer+ iNKTs in the liver (Figure 1A&E) but not in the spleen (Figure 1A)
When expressed as an absolute number of cells but not as a percentage, iNKTs were slightly increased in white adipose tissue (WAT). This difference between percentage and numbers of iNKTs in the WAT was attributable to the greater number of WAT stromal vascular cells isolated from obese animals, such that an increase in WAT iNKT numbers was dwarfed by much larger increases in other infiltrating populations; this is consistent with the dramatic increase of macrophages and other inflammatory cells observed during obesity [3]
Summary
It has become increasingly clear that molecules and cells classically associated with the immune system have important roles in maintenance of whole body energy metabolism. Several mouse strains deficient in cytokines or chemokines are either protected from or prone to obesity and insulin resistance [1]. Nearly every cell type classically associated with the immune system—macrophages [2,3], conventional T cells [4,5,6], eosinophils [7], mast cells [8], B cells [9]—has been implicated in the control or pathogenesis of obesity-associated morbidity. An overarching rationale for how and why the various cells of the immune system orchestrate metabolic processes remains elusive
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