Murine Neonatal Lymphocytes Show Rapid Early Cell Cycle Entry and Cell Division

Abstract

Neonatal animals are highly susceptible to infectious agents. At least part of this susceptibility is due to the virtual absence of immunological memory in newborns. One of the hallmarks of memory is the rapidity of the response. We show in this study that neonates may make up for their lack of memory, at least in part, by the rapid entry of large proportions of naive lymphocytes into the cell cycle. Following activation, greater percentages of both CD4+ and CD8+ neonatal, as compared with adult, lymph node cells showed early cell cycle entry; this was assessed by propidium iodide staining, CFSE labeling profiles, [3H]thymidine uptake, and up-regulation of early activation markers. This rapid cycle entry was observed following polyclonal activation with anti-CD3 or with PMA and ionomycin and in both C57BL/6 and BALB/c mice. Stimulation with specific peptide also elicited more rapid proliferative responses from neonatal vs adult TCR transgenic CD4+ cells. In addition, more rapid cycle entry was observed in vivo, in lymphopenic RAG2−/− hosts. For both CD4+ and CD8+ cells, this phenomenon was observed out to 3 wk of life, although the differences between neonatal and adult cells became smaller with increasing time postbirth. These properties of peripheral neonatal T cells appeared to be inherited from their thymic precursors, because CD4+8− single-positive cells in the neonatal thymus also showed more rapid cycle entry, compared with their counterparts in the adult thymus. Interestingly, rapid early cycling was also observed among activated neonatal B cells, compared with adult B cells. Thus, early cell cycle entry by large proportions of cells may allow the naive lymphocyte population to efficiently mobilize responses against the broad range of pathogens first encountered in neonatal life.

Transplantation of newborn thymus plus hematopoietic stem cells can rescue supralethally irradiated mice

“…Although we did not examine the mechanism of the rescue directly, given the above results, the high growth activity of NT is likely to be critical in the elevation of IL-7 and KGF. In fact, although the size of the AT graft did not change or slightly decreased after reconstitution, 17 grafted NT or FT grew rapidly under the renal capsule with high proliferative acivity, 32,33 and the size became close to the grafted AT by 8 weeks after transplantation, even though their initial volume and weight was about 1/10 less than the AT (data not shown). The activity may also help regenerate or completely repair damaged organs in SLI mice.…”

“…38,39 In this respect, T cells from the NT were shown to be highly proliferative and functional for the production of various cytokines compared with AT. 32,33 This might also facilitate the rescue of SLI mice. Although we did not examine the mechanism of the rescue directly, given the above results, the high growth activity of NT is likely to be critical in the elevation of IL-7 and KGF.…”

“…31 In the present study, we attempted to rescue SLI mice using HSC transplantation plus thymus transplantation from variously aged donors, since the functions of the thymus greatly differ with age. 32,33 We here show that the transplantation of newborn liver cell (NLCs) plus newborn thymus (NT) can most effectively rescue SLI mice. It is likely that the high production of IL-7 by NT transplantation plays an important role in the induction of CD4 þ T cells.…”

Fetal and neonatal gene therapy: benefits and pitfalls

“…This may be due to the following: (i) the reduced number of immune cells in early life; (ii) the developmental immaturity of cells participating in the immune response; (iii) the deviance of the early immune response from that of the adult, with particular bias towards a T H 2 rather than a T H 1 response; and (iv) the absence of memory cells due to the naivety of the immune system (see Adkins et al 28 and references cited therein). Selected studies illustrating such mechanisms are cited below.…”

Effects of Allogeneic Hematopoietic Stem Cell Transplantation Plus Thymus Transplantation on Malignant Tumors: Comparison Between Fetal, Newborn, and Adult Mice

“…The proliferative activity of T cells from the fetal and newborn thymus is much higher than in those from adults [16,17], whereas the level of cytokine production increases with age [18]. In this regard, we have recently found that supralethally irradiated mice are rescued by [newborn liver cell transplantation (NLT) þ newborn TT (NTT)] more efficiently than by [BMT þ adult TT (ATT)] or [fetal liver cell transplantation (FLT) þ fetal TT (FTT)] [12].…”