Abstract

Abstract Invariant natural killer T cells (iNKT cells) are a conserved population that expresses a canonical TCR α rearrangement, Vα14-Jα18 in mice, and recognizes CD1d+glycolipid antigens. Different subsets of iNKT cells have been reported, including NKT1, NKT2 and NKT17 cells. We have shown that a small alteration in E protein activity during development of iNKT development results in a decrease in the development of NKT1s at the expense of NKT2 and NKT17 cells. E protein activity is regulated by the expression levels of Id proteins, which are induced downstream TCR signals during positive selection. Therefore, we hypothesized that changes in TCR signal strength may influence NKT subset differentiation. To test this we have used a gain-of-function, loss-of-function model, where signal strength is modified at the level of Lck by expression of a constitutive active (dLGF) or catalytically inactive (dLGKR) Lck mutant at low levels. Our results show that in dLGKR mice, which have less Id induction and increased E protein activity during positive selection, the percentage of NKT2 in the thymus is increased. In contrast, in dLGF(Balb/c) mice there is a dramatic shift from the NKT2 and NKT17 subsets in the thymus towards the NKT1 subset. These results suggest that TCR strength may bias NKT subset differentiation, but it is unclear what determines signal strength during NKT positive selection. Differential Vβ usage affects NKT TCR affinity for different ligands, and there is evidence that Vβ usage is biased (i. e. Vβ7 is overrepresented in NKT2). However, despite the major shift in subset representation in dLGF mice, there are only minor changes in the Vβ usage. Therefore, Vβ expression is unlikely to to be the only factor influencing TCR signal strength.

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