Tissue-resident NK cells differ in their expression profile of the nutrient transporters Glut1, CD98 and CD71

Abstract

Metabolism is a critical basis for immune cell functionality. It was recently shown that NK cell subsets from peripheral blood modulate their expression of nutrient receptors following cytokine stimulation, demonstrating that NK cells can adjust to changes in metabolic requirements. As nutrient availability in blood and tissues can significantly differ, we examined NK cells isolated from paired blood-liver and blood-spleen samples and compared expression of the nutrient transporters Glut1, CD98 and CD71. CD56bright tissue-resident (CXCR6+) NK cells derived from livers and spleens expressed lower levels of Glut1 but higher levels of the amino acid transporter CD98 following stimulation than CD56bright NK cells from peripheral blood. In line with that, CD56dim NK cells, which constitute the main NK cell population in the peripheral blood, expressed higher levels of Glut1 and lower levels of CD98 and CD71 compared to liver CD56bright NK cells. Our results show that NK cells from peripheral blood differ from liver- and spleen-resident NK cells in the expression profile of nutrient transporters, consistent with a cell-adaptation to the different nutritional environment in these compartments.

NK cell metabolism

“…CD56 bright cells, probably by virtue of increased cytokine receptor expression, are more responsive to metabolic change and upregulated several metabolic markers more strongly that CD56 dim cells in response to cytokine stimulation . Recently, this has been confirmed for peripheral blood NK cells and extended with similar findings among tissue resident (CD56 bright , liver or spleen) NK cells . Within the CD56 dim subset, further subsets can be further discriminated.…”

“…In particular, glutamine uptake through SLC7a5, an amino acid transporter that is strongly upregulated on NK cells in response to cytokine, was key for activation and maintenance of c‐Myc signaling. There is increasing evidence that nutrient receptors, such as the transferrin receptor (CD71), l ‐amino acid transporter SLC7a5 (also known as LAT1; it is the active subunit that forms a heterodimer with the chaperone chain, CD98), the glutamine transporter (SLC1a5), as well as the glucose transporter (Glut1), are all expressed and upregulated on activated NK cells where they can impact on immune signaling …”

“…5 Recently, this has been confirmed for peripheral blood NK cells and extended with similar findings among tissue resident (CD56 bright , liver or spleen) NK cells. 29 Within the CD56 dim subset, further subsets can be further discriminated. Licensed (functional) and unlicensed (hyporesponsive) NK cells can be identified based on the presence or absence of complementary KIR/HLA receptors.…”

“…There is increasing evidence that nutrient receptors, such as the transferrin receptor (CD71), L-amino acid transporter SLC7a5 (also known as LAT1; it is the active subunit that forms a heterodimer with the chaperone chain, CD98), the glutamine transporter (SLC1a5), as well as the glucose transporter (Glut1), are all expressed and upregulated on activated NK cells where they can impact on immune signaling. 5,10,26,29,41…”

NK Cell Metabolism and the Potential Offered for Cancer Immunotherapy

“…A number of studies have demonstrated that CD56 bright cells are more metabolically responsive, whether they are from peripheral blood or tissue resident [22,27]. While CD98 is expressed on all NK cells (and is upregulated in response to cytokine), CD71 is generally only present at low levels and increases preferentially on CD56 bright cells upon activation.…”