LONG-TERM CULTURE OF MONOCLONAL HUMAN T-LYMPHOCYTES - MODELS FOR IMMUNOSENESCENCE

Human monoclonal T lymphocyte populations maintained in long-term cult ure by intermittent reactivation via the antigen receptor and supplied with exogenous interleukin 2 manifest finite proliferative lifespans. T lymphocytes cloned from mature peripheral T cells of adult donors w ere constantly lost from the time point of their first isolation up to an estimated maximum of 80 population doublings (PD) for the longest lived. T lymphocytes cloned from T cell progenitors in bone marrow, on the other hand, survived For a maximum of ca. 100 PD, One facet of th e functional capacity of cells derived from these two different source s was assessed by measuring their autocrine proliferation after mitoge nic stimulation. For a majority of T cell clones (TCC), autocrine prol iferative capacity decreased as a function of culture age, becoming ab sent by 50 PD for adult-derived-TCC and by 70 PD for bone marrow-deriv ed TCC, thereby clearly occurring prior to the end of the proliferativ e life spans of the clones. Limiting dilution frequency analysis showe d that the number of autocrine proliferative precursors within these m onoclonal populations declined with age, paralleling loss of autocrine proliferative capacity in the 'bulk' clones. Of a variety of surface structures monitored during culture ageing of TCC, the density of expr ession of the coreceptor molecule CD28 was found to correlate with dec reasing autocrine proliferative capacity in two-thirds of the clones. Thus, at least for a fraction of monoclonal human T lymphocytes, decre asing autocrine proliferative capacity, a measure of clonal expansion, may correlate with decreasing numbers of CD28 molecules expressed on the surface and therefore presumably with the strength of costimulator y signal delivered via this important coreceptor.