CD1d-mediated Recognition of an α-Galactosylceramide by Natural Killer T Cells Is Highly Conserved through Mammalian Evolution

TLDR

NK T cells are a lymphocyte subset with a distinct phenotype, an invariant TCR, and reactivity to CD1. Our data suggest that α‑GalCer could modulate human immune responses by activating the highly conserved NK T cell subset implicated in autoimmune disease and tumor control. Mouse or human CD1 molecules present α‑GalCer to NK T cells from either species. Mouse and human NK T cells recognize each other’s CD1d and both species’ CD1 molecules presenting α‑GalCer, and α‑GalCer stimulation expands invariant Vα24+ NK T cells and elicits large cytokine release, highlighting the system’s fundamental conservation.

Abstract

Natural killer (NK) T cells are a lymphocyte subset with a distinct surface phenotype, an invariant T cell receptor (TCR), and reactivity to CD1. Here we show that mouse NK T cells can recognize human CD1d as well as mouse CD1, and human NK T cells also recognize both CD1 homologues. The unprecedented degree of conservation of this T cell recognition system suggests that it is fundamentally important. Mouse or human CD1 molecules can present the glycolipid α-galactosylceramide (α-GalCer) to NK T cells from either species. Human T cells, preselected for invariant Vα24 TCR expression, uniformly recognize α-GalCer presented by either human CD1d or mouse CD1. In addition, culture of human peripheral blood cells with α-GalCer led to the dramatic expansion of NK T cells with an invariant (Vα24+) TCR and the release of large amounts of cytokines. Because invariant Vα14+ and Vα24+ NK T cells have been implicated both in the control of autoimmune disease and the response to tumors, our data suggest that α-GalCer could be a useful agent for modulating human immune responses by activation of the highly conserved NK T cell subset.