Graham Pawelec ¹, Ed Remarque ², Yvonne Barnett ³, Rafael Solana ⁴

1 University of Tübingen, Tübingen, FRG ², University of Leiden, Leiden, Holland ³, University of Ulster, Coleraine, Northern Ireland ⁴, University of Córdoba, Córdoba, Spain

Received 12/29/97 Accepted 1/5/97

12. PERSPECTIVES

We suggest the following simple interpretation (figure 1):

Figure 1. Senescence affects T cell differentiation and function at different levels. First, there is a decreased number of bone marrow precursors migrating to the thymus. In the involuting thymus the function of both the thymocytes and the cells from the microenvironment is compromized in the ability to support T cell differentiation, resulting in a decreased output of new naive T cells in the elderly. Long lived naive T cells suffer antigen-independent post-mitotic senescence even in their quiescent state. T cells which have been activated and become memory cells are maintained in a proliferative state and are, therefore, subjected to replicative senescence and clonal exhaustion. These changes result in a defective capacity of T cells to collaborate in other aspects of the immune response, hematopoiesis and lymphopoiesis.

As the organism ages, the output of T cell precursors from the BM decreases. Those precursors that enter the progressively involuting thymus are doubly compromized in their ability to generate new T cells: firstly because of their intrinsic deficiencies and secondly because of the reduced thymic function. There is therefore a quantitative and qualitative component to the dysregulated generation of naive T cells which becomes greater as the individual ages. In addition, naive cells produced by the thymus of the individual when young and surviving for extended periods in the periphery, themselves age even in the quiescent state. T cells which have been activated at some time during the life of the individual may remain present as memory cells and respond to rechallenge by antigen. However, because memory cells are maintained in a proliferative state even in the absence of specific antigen, they are subject to the aging limitations of proliferating cells and eventually undergo "replicative senescence". Even before they reach this terminal state, their function is altered and impaired compared to young cells, for example in terms of their increased susceptibility to activation-induced cell death. Since these cells cannot be so easily replaced by freshly activated naive cells as efficiently in old as in young individuals, the resulting immune response is reduced and generation of memory compromized in the elderly.