Repertoire development and the control of cytotoxic/effector function in human gammadelta T cells.

T cells develop into two major populations distinguished by their T cell receptor (TCR) chains. Cells with the alphabeta TCR generally express CD4 or CD8 lineage markers and mostly fall into helper or cytotoxic/effector subsets. Cells expressing the alternate gammadelta TCR in humans generally do not express lineage markers, do not require MHC for antigen presentation, and recognize nonpeptidic antigens. We are interested in the dominant Vgamma2Vdelta2+ T cell subset in human peripheral blood and the control of effector function in this population. We review the literature on gammadelta T cell generation and repertoire selection, along with recent work on CD56 expression and defining a cytotoxic/effector lineage within the phosphoantigen-reactive Vgamma2Vdelta2 cells. A unique mechanism for MHC-independent repertoire selection is linked to the control of effector function that is vital to the role for gammadelta T cells in tumor surveillance. Better understanding of these mechanisms will improve our ability to exploit this population for tumor immunotherapy.

Control of CD56 expression and tumor cell cytotoxicity in human Vgamma2Vdelta2 T cells.

BACKGROUND: In lymphocyte subsets, expression of CD56 (neural cell adhesion molecule-1) correlates with cytotoxic effector activity. For cells bearing the Vgamma2Vdelta2 T cell receptor, isoprenoid pyrophosphate stimulation leads to uniform activation and proliferation, but only a fraction of cells express CD56 and display potent cytotoxic activity against tumor cells. Our goal was to show whether CD56 expression was regulated stochastically, similar to conventional activation antigens, or whether CD56 defined a lineage of cells committed to the cytotoxic phenotype. RESULTS: Tracking individual cell clones defined by their Vgamma2 chain CDR3 region sequences, we found that CD56 was expressed on precursor cytotoxic T cells already present in the population irrespective of their capacity to proliferate after antigen stimulation. Public T cell receptor sequences found in the CD56+ subset from one individual might appear in the CD56- subset of another donor. The commitment of individual clones to CD56+ or CD56- lineages was stable for each donor over a 1 year interval. CONCLUSION: The ability to express CD56 was not predicted by TCR sequence or by the strength of signal received by the TCR. For gammadelta T cells, cytotoxic effector function is acquired when cytotoxic precursors within the population are stimulated to proliferate and express CD56. Expression of CD56 defines a committed lineage to the cytotoxic phenotype.