T-cell receptor gene rearrangements and expression in normal human large granular lymphocytes (LGL) and their pathological expansions

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 Tβ gene in its unrearranged germline configuration. Expression of Tα and Tβ genes was not detectable. The organization of Tγ 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 Tγ-LPD, is characterized by expansion of cells very similar to LGL for morphology, phenotype, and functional activity. Of 17 patients with Tγ-LPD studied for T-rec rearrangement, 15 displayed rearrangement of Tβ and Tγ 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 Tγ-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 TγLPD are monoclonal, presumably neoplastic, lymphoproliferative disorders.