Adult naive T cells, which are at rest in normal conditions, proliferate strongly when transferred to lymphopenic hosts. In neonates, the first mature thymocytes to migrate to the periphery reach a compartment devoid of preexisting T cells. We have extensively analyzed the proliferation rate and phenotype of peripheral T cells from normal C57BL͞6 and T cell antigen receptor transgenic mice as a function of age. We show that, like adult naive T cells transferred to lymphopenic mice, neonatal naive T cells proliferate strongly. By using bone-marrow transfer and thymicgraft models, we demonstrate that the proliferation of the first thymic emigrants reaching the periphery requires T cell antigen receptor-self-peptide͞self-MHC interactions and is regulated by the size of the peripheral T cell pool. P eripheral T cells expand strongly after transfer to lymphopenic hosts (1, 2). This proliferation has been considered as a homeostatic mechanism that fills the peripheral T cell pool. It was initially suggested that homeostatic T cell proliferation was restricted to activated͞memory T cells. Indeed, most authors inferred that naive and memory T cell pools would be regulated independently. The memory T cell pool would be renewed and filled by proliferation of preexisting activated͞memory cells, whereas only continuous output of naive T cells by the thymus could generate a full compartment of truly naive T cells (3). This theory is supported by the observation that a significant proportion of memory T cells proliferate in normal mice, whereas naive T lymphocytes do not cycle in normal conditions (4-8).Nevertheless, using monoclonal naive T cells from T cell antigen receptor (TCR) transgenic mouse strains and purified polyclonal naive T cells from normal mice, it has recently been shown that naive T cells proliferate when transferred to lymphopenic hosts (8-21). Such peripheral T cell expansion would be depend on self-peptide-specific, low-affinity interactions similar to those required for positive selection in the thymus (10-12), although other reports do not support this view (13). By following the long-term fate of naive T cells transferred to lymphopenic hosts (rag-deficient, CD3 -deficient, and irradiated normal mice), we and others have observed that the transferred cells fail to fill the peripheral naive T cell pool. Indeed, absolute numbers of recovered T cells are far below those found in the full peripheral naive T cell pool of a normal mouse. Moreover, injected naive T cells acquire a memorylike phenotype that remains stable with time, despite the absence of foreign antigenic stimulation, and their functional capacities are modified, enhanced, or abolished (18-21). Recent studies have demonstrated a role of IL-7, IL-12, and p56 lck in the proliferation of naive T cells in lymphopenic mice (22)(23)(24)(25), but the mechanisms underlying this process are not fully understood.Furthermore, it is crucial to show the physiological relevance of this mechanism. Indeed, injection of purified naive T cells to irradiated or...

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