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. Author manuscript; available in PMC: 2014 May 19.
Published in final edited form as: Immunity. 2012 Feb 24;36(2):163–165. doi: 10.1016/j.immuni.2012.02.005

Losing TREC with age

Shirley L Zhang 1, Avinash Bhandoola 1,*
PMCID: PMC4026262  NIHMSID: NIHMS477356  PMID: 22365662

How long do naïve T cells live and how are they replenished? A short lifespan for naïve T cells would necessitate faster rates of replenishment, whereas increased lifespan would accommodate slower rates of replenishment. Work in the current issue by Tesselaar and colleagues examines the longevity of naïve T cells. Their data suggest that mechanisms maintaining T cells with naïve phenotypes might differ in humans and mice (den Braber et al., 2012).

The lifespan of mice is approximately two years, whereas humans live much longer. Do the naïve T cells of mice and humans also have different lifespans? Tough and Sprent measured T cell turnover in mice by using bromodeoxyuridine (BrdU) treatment to label dividing cells. These results indicated that naïve T cells in mice persisted for several weeks on average without dividing (Tough and Sprent, 1994). Two different approaches were taken to measure human naïve T cell turnover. Michie et al. examined T cells from patients receiving therapeutic irradiation and assayed for loss of cells with chromosomal damage as a measure of time between mitosis in T cells (Michie et al., 1992). Hellerstein and colleagues administered deuterated water (2H2O) to human subjects. The incorporation of the 2H-isotope into replicating DNA was measured by mass spectrometry to determine the fraction of labeled cells (Neese et al., 2002). Both of these studies found human T cells to have an astonishing (to mouse immunologists) half-life on the order of years instead of weeks.

Tesselaar and colleagues repeat and extend these studies in both mice and humans. They use deuterated water labeling to determine turnover of naïve T cells. In this study, the half-life of CD4 and CD8 T cell populations in mice was 7 and 11 weeks respectively. Earlier results from the same group indicated that human naïve CD4 T cells have an average half-life of six years whereas CD8 T cells have an average half-life of nine years (Vrisekoop et al., 2008). Together these results confirm the much shorter lifespan of naïve T cells in mice compared to humans.

The different lifespans of naïve T cells in mice and humans might indicate distinct mechanisms to maintain naïve T cell populations. The authors examined the relative contributions of naïve T cell generation by the thymus and T cell proliferation in the periphery. Similar to previous studies, the authors quantified T cell receptor excision circles (TRECs) to determine thymic output (Douek et al., 1998). TRECs are DNA by-products of somatic rearrangement of TCR genes during T cell development in the thymus. Because TRECs do not replicate during cellular proliferation in the periphery, the TREC content of T cell populations correlates with thymic output assuming TRECs are stable. Tesselaar and colleagues measure the average TREC content in naïve T cells of both mice and humans. They find that naïve T cells of mice have comparable TREC content whether they are obtained from young or old mice (Figure 1). In humans, in contrast, the TREC content of T cells with naïve phenotype is high in neonates but declines with age.

Figure 1. Diagram of TREC content in naïve T cell populations.

Figure 1

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The average TREC content of naïve T cells remains comparable in both young and old mice. In humans, TREC content of T cells with naïve phenotype declines with age.

What might these findings mean? The authors estimate the fraction of cells that were originally thymically derived using the average TREC content of the naïve T cell population. Mathematical modeling of the data indicates that up to 90% of human “naïve” T cells are generated through proliferation in the periphery in aged individuals. From these data, the authors suggest that the mechanisms maintaining phenotypically naïve T cells might be fundamentally different in mice and humans. Hence, thymic output maintains naïve T cell populations in mice, and thymic involution and loss of thymic output results in reductions in frequencies of naïve T cells in the periphery. In contrast, human T cells may divide in the periphery without losing their naïve phenotype based on current markers. Such a possibility had been previously suggested in other human studies of naïve T cells (Dutilh and de Boer, 2003; Kilpatrick et al., 2008). One consequence of maintaining T cell populations chiefly through peripheral expansion would be decreasing TCR repertoire diversity with age.

The use of TRECs to define undivided naïve T cells presents some uncertainties. As the authors discuss, the loss of TRECs in human T cell populations over time may not indicate cell division; instead, it might indicate a failure to maintain extrachromosomal DNA during the long lifespan of human naïve T cells. However, the results of Tesselaar and colleagues do highlight the vast difference in scale between human and mouse T cell lifespans, indicating different mechanisms might exist to maintain T cells in humans and mice. This suggests that the mouse may not be always be a suitable animal model for a human. Several groups have worked to establish humanized mouse models in which human stem cells are used to reconstitute hematopoietic compartments of immunodeficient mice with human immune cells. Mice with a human immune system would allow study of human diseases such as HIV as well as allow study of environmental and cell-intrinsic determinants of T cell lifespan. However, in humanized mice the naïve T cell turnover rate has been suggested to be even higher than the rate seen with normal mouse T cells; the reasons for this are not well understood (Legrand et al., 2006). Another implication of this present study is that better markers are needed to identify undivided naïve T cells in humans, as many T cells presently considered naïve may have divided in the periphery. In mice, homeostatic proliferation of naïve T cells generates cells functionally differing from naïve T cells (Haluszczak et al., 2009). It is unknown whether human T cells proliferating in the periphery with a naïve phenotype are equivalent to naïve T cells exported from the thymus. Together, these data emphasize the need for improved animal models and other tools to better understand how human T cell populations are generated and maintained.

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