The study of regulatory T cells has undergone a renaissance, driven in part by the description of the CD4+CD25+ subset. Natural killer T (NKT) cells constitute a second subpopulation that may have important regulatory functions. NKT cells are typically identified as lymphocytes that co-express NK1.1 and a T-cell receptor (TCR), but in mice the majority of these cells have additional properties, including an invariant CDR3a formed by rearrangement of Va14 to Ja18 (formerly Ja281) that associates preferentially with diverse rearrangements of either Vb8, Vb7 or Vb2, and reactivity to CD1d. Currently, the natural ligand(s) presented by CD1d for Va14i T cell stimulation are unknown. However, the Va14i T cell response to CD1d is greatly augmented by the glycosphingolipid a-galactosyl ceramide (a-GalCer), isolated from the marine sponge Agelas Mauritanius.
The Va14i NKT cells exhibit unique functional properties, most notably the production of large amounts of IL-4 and other cytokines within 90 minutes of TCR stimulation in vivo. Because of their potent ability to secrete cytokines rapidly, Va14i NKT cells are believed to have an immune regulatory role. The results from the study of several animal models of autoimmune diseases, as well as studies of human patients with type I diabetes and other autoimmune diseases support this hypothesis. Va14i NKT cells might also be involved in some circumstances in the prevention of tumor metastases and the response to some infectious agents.
Ongoing efforts in the laboratory address 4 major questions:
First, we reported recently that the development of NKT cells in the thymus branch off from the conventional T cells at the double-positive stage where random rearrangements of the TCRs take place. Studies are underway to understand the specific signals required by uncommitted double-positive precursors to decide to become a NKT cells.
While T cells develop in the thymus, they undergo two processes of selection. The first one, known as positive selection, ensure that mature lymphocytes exported to the peripheral organs will express TCR capable of interacting properly with the major histocompatibility molecules that present the antigenic peptides. The second one, known as negative selection, makes sure that immature T cells expressing TCR that react strongly with ubiquitous self-antigens are eliminated.
Mature Va14i NKT cells demonstrate some degrees of auto-reactivity for the CD1d molecules in absence of added antigens. Our studies address the question of whether or not Va14i NKT cells also undergo negative selection during their development in the thymus. The frequency of Va14i T cells is reduced in a variety of autoimmune diseases. Because of their apparent importance for immune regulation, it is critical to define the factors governing the maintenance of the Va14i T cell population. We have shown that the homeostasis of Va14i NKT cells was not dependent on CD1d expression, and was not affected by the presence of host NKT cells. Additionally, we found that IL-15 was important in expansion and/or survival of Va14i NKT cells, with IL-7 playing a lesser role. Further experiments are designed to determine what are the other factors involved in the control of NKT cells homeostasis.
Finally, our recent studies showed that Va14i NKT cells are poised to produce both IL-4 and IFNg and that this cytokine output cannot be altered by methods that polarize conventional CD4+ T cells. Our lab is committed to understanding the molecular mechanisms involved in the cytokine secretion by Va14i NKT cells.