Naive T cells proliferate strongly in neonatal mice in response to self-peptide/self-MHC complexes

Abstract

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...

CD25+CD4+ Regulatory T Cells and Memory T Cells Prevent Lymphopenia-Induced Proliferation of Naive T Cells in Transient States of Lymphopenia

“…The lymphopenia observed in NOD mice genetically disposed to develop diabetes is also not comparable with that seen in T cell-deficient hosts (18). During a short time frame in the neonatal phase, T cells seeding the periphery will encounter a severely lymphopenic environment, but the effect of lymphopenia-induced proliferation during this short time period remains unclear and appears minor overall (32,34). Severe induction of lymphopenia may thus be restricted to clinical interventions such as radiation treatment or treatment with cytotoxic drugs that may, in addition to depleting mature peripheral T cells, also affect T cell replenishment by the thymus.…”

“…Similarly, irradiated wild-type hosts may present higher amounts of commensal bacterial Ags due to irradiation-induced gut damage as well as the release of multiple cytokines that may influence lymphopenia-induced proliferation of adoptively transferred naive T cells (25). Second, in contrast to experimental models with genetically lymphopenic or irradiated hosts, the physiological occurrence of lymphopenia throughout an individual's lifetime due to viral infection (26 -28), therapy-related toxicity (29 -31), or age-related changes (neonatal conditions (32)(33)(34) and aging) rarely results in the depletion of all peripheral T cells. However, the incidence of lymphopenia-induced proliferation and homeostasis of peripheral T cell pools under conditions of partial and transient lymphopenia have not been studied in detail.…”

Memory Phenotype of CD8+ T Cells in MHC Class Ia-Deficient Mice

“…This is evident in the thymus of these mice which contain ϳ15% of SP CD8 cells seen in B6 mice. It has been noted that SP cells in neonatal mice proliferate strongly and display a CD44 high phenotype, reflecting the lymphopenic environment that they are exposed to (25,26). We have compared the phenotype of splenic SP CD8 T cells in B6 and B6.K bϪ D bϪ animals and observed that on day 1 both strains contained a predominance of cells that are CD44 high CD62L low .…”

γδ T Cell Homeostasis Is Controlled by IL-7 and IL-15 Together with Subset-Specific Factors

“…An additional situation in which homeostatic proliferation may be part of normal physiology is during ontogeny, when the first waves of thymusderived T cells begin populating secondary lymphoid organs. Indeed, a recent study using bone marrow and thymic-graft models showed that early thymic emigrants expressing ␣␤ TCR proliferate in neonatal mice in a way regulated by the interaction with selfpeptide/MHC and by the size of the peripheral T cell pool (38). Our study suggests that ␥␦ T cells, known to be among the first to be produced early in life, are also likely to proliferate in the T cell-devoid periphery of neonates, and identifies IL-7 and IL-15 as possible modulators of such expansion.…”