The lineage to which normal large granular lymphocytes/natural killer (LGL/NK) cells belong is controversial; in fact they share some surface markers and functional activities with monocytes, but also with T lymphocytes. The relationship of LGL to the T cell lineage by analysis with the T cell receptor (T-rec) gene has been investigated. Pure preparations of human LGL and their CD11 + CD8-and CD11-CD8 + subsets had the T13 gene in its unrearranged germline configuration. Expression of Tc~ and T13 genes was not detectable. The organization of Ty gene, which is of particular importance because it occurs early in T cell ontogeny, was also found in its germline configuration.
A rare type of lymphoproliferative disorder, termed TT-LPD, is characterized by expansion of cells very similar to LGL for morphology, phenotype, and functional activity. Of 17 patients with Ty-LPD studied for T-rec rearrangement, 15 displayed rearrangement of T13 and Ty loci and were CD3+ (14/15 had monoclonal rearrangement), while 2 cases were in germline configuration and were CD3-. Similarly to very small subsets of CD3+ LGL recently described, most Ty-LPD cases are CD3+ and have T-rec genes rearranged. These data suggest that either a subset of LGL or a particular step of differentiation may be related to the T cell lineage; they also demonstrate that, in contrast to previous views, most TTLPD are monoclonal, presumably neoplastic, lymphoproliferative disorders.