Longevity in vitro of human CD4+T helper cell clones derived from young donors and elderly donors, or from progenitor cells: age-associated differences in cell surface molecule expression and cytokine secretion

The effectiveness of the adaptive immune system relies upon extensive proli feration of an initially small number of antigen-specific T cells. At the e nd of a successful response, the majority die by apoptosis and a small mino rity joins the memory cell pool. Upon re-challenge with antigen, these memo ry cells must again undergo clonal expansion in order to mediate an effecti ve response. Thus, T cells are subjected to marked proliferative stress whi ch may result in clonal exhaustion due to replicative senescence. In other systems made up of rapidly proliferating cells (e.g. in the gut) individual clones: are identical and are replaced at the end of their lifespan by dif ferentiation from a stem cell reservoir. However, because of the unique clo nal distribution of antigen receptors on T cells, mere replacement with oth er T cells is not sufficient to maintain the integrity of the system. Moreo ver, the very source of new T cells decreases with age (due to thymic invol ution). Therefore, the adaptive immune system may be uniquely susceptible t o the deleterious effects of replicative senescence. Particularly in humans , in vivo studies of the behaviour of individual T-cell clones in the body is difficult. However, T-cell longevity, measured as proliferative capacity in terms of population doublings, can be usefully modelled at the clonal l evel in vivo. This paper discusses the surprisingly little that is known ab out the average longevity, variation between clones, and the maximal longev ity of human T cells under clonal culture conditions in vitro. From our own studies, we show that average lifespan of human T cells is as little as 17 PD; however, established clones reach 35 PD on average, with maximum longe vity generally ill the region of 60-80 PD, regardless of the source of the cloned cells. Expression of surface molecules in general did not differ str ikingly between young and old donors, but the frequency of clones secreting IL-10, and the amount secreted pet clone was higher in the elderly than in the young. Conversely, the frequency of clones secreting IL-6 and the amou nt secreted per clone was higher in the young.