NKT cells: In the beginning…

Abstract

Invariant natural killer T (iNKT) cells as we know them today are a unique subset of mature T cells co-expressing a semi-invariant Va14/Vb8 TCR and surface markers characteristic of NK cells. The semi-invariant TCR on iNKT cells recognizes glycolipids bound to monomorphic CD1d molecules, leading to rapid cytokine production. The purpose of this historical perspective is to describe how a series of seemingly unrelated findings in the late 1980s and early 1990s crystallized in the discovery of iNKT cells. The story is told from a personal viewpoint, with a particular effort to place both breakthroughs and misinterpretations in the context of their era. IntroductionIn the summer of 1987 two groups independently reported the identification of a mysterious subset of CD4 -CD8 -(double-negative, DN) thymocytes that overexpress the TCR Vb8 gene segment [1,2]. A third report followed shortly thereafter [3]. Around the same time an unusual invariant TCR Va14-Ja18 rearrangement was cloned from a panel of keyhole limpet hemocyaninspecific suppressor T cell hybridomas [4,5]. Collectively these studies provided the first glimpse of what are now known as invariant natural killer T (iNKT) cells, but the road to that conclusion proved to be unusually long and winding. The purpose of this "historical" feature is to recount this process of discovery from a personal viewpoint, highlighting both breakthroughs and misinterpretations along the way. Vb8-biased DN thymocytesGiven that most iNKT cells express CD4 and are preferentially localized in the liver, it may seem surprising that they were first identified as a DN subset in the thymus. However, two independent sets of circumstances contributed to this discovery. First a number of groups, including our own, were actively dissecting thymus subsets in the mid 1980s using flow cytometry and a growing battery of monoclonal antibodies (mAb). It became clear from the work of Fowlkes and Mathieson [6] that the very small DN subset (2-3% of thymocytes) contained immature precursors capable of differentiating into all other thymus subsets. This finding prompted intense scrutiny of the DN population by most groups working on T cell development.The second key catalyst to the discovery of iNKT cells was the successful production of the first allotypic mAb to the TCR by the Kappler/Marrack [7] and Bevan [8] groups. Although the TCRb and TCRa chains had been molecularly cloned, by this time no mAb to Vb domains had been identified. By pure serendipity these mAb were both directed against the Vb8 domain that is dramatically over-represented among iNKT cells. Thus it rapidly became clear that the DN thymocyte subset had a TCR repertoire that was heavily biased towards Vb8 [1][2][3].With hindsight it is interesting to note that this first glimpse of iNKT cells was interpreted incorrectly by both groups that made the initial discovery. Based on the dogma that DN thymocytes were immature, we speculated that the Vb8-biased subset might arise from preferential usage of certain Vb domains early in deve...

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