Viruses and T Cell Turnover: Evidence for Bystander Proliferation

Most T cells activated during typical immune responses differentiate to become short-lived effector cells which disappear after clearance of antigen. However, priming with antigen generally causes antigen-specific T cells to persist at greater than pre-immunization levels for long periods of time, thus leading to immunological memory. To understand the cellular basis for immune memory it is of key importance to determine the factors which regulate the generation and persistence of memory cells. Two basic mechanisms have been proposed to explain the persistence of memory cells. The first is that memory cells are intrinsically long-lived and require no stimulus for their continued survival. The opposing view is that, rather than existing autonomously, memory cells require periodic stimulation through their antigen receptors, this could be mediated by encounter with the original priming antigen, which may persist or be re-introduced to the host, or by cross-reactive environmental antigens. For viruses and CD8 super(+) cells, a strict requirement for specific antigen in maintaining memory has been ruled out by the finding that virus-specific CD8 super(+) cells persist indefinitely, at least at a population level, after adoptive transfer to virus-free hosts. However, as acknowledged by the authors of these studies, the data do not rule out the possibility that memory T cells may persist through low affinity interactions with cross-reactive environmental antigens; reactivity to these antigens would reflect the increased expression of adhesion molecules on memory T cells, thus leading to heightend sensitivity to stimulation through the TCR. In considering the issue of how memory cells persist, it is important to understand the kinetic behaviour and life span of these cells. In this paper, we review our recent work on the factors controlling T cell turnover in normal and virus-infected mice.