The maintenance of the naive T cell pool during homeostasis is differently regulated in humans and wildling mice

Abstract

Understanding how naive T cells are maintained during healthy aging is important to unravel the effects of lymphopenic conditions on naive T cell dynamics. Naive T cells can be produced in two different ways: through production of naive T cells by the thymus or through peripheral division. The contribution of the thymus to naive T cell production can be quantified through the measurement of T cell receptor excision circles (TRECs). TRECs are episomal DNA circles, formed during rearrangement of T cell receptor (TCR) genes in both human and murine T cells. TRECs are stable, do not replicate during cell division and are exclusively from thymic origin.

As the TREC content of human naive T cells declines with age, it is thought that the human naive T cell pool is mainly maintained through peripheral division. However, the decline in TREC content could also be the result of a bias in the human naive T cell population that increases with age. Previously, when the TREC content of human naive T cells was measured, stem-cell like memory T cells (Tscm cells) were still included in the human naive T cell compartment. Relative to truly naive T cells, the TREC content of Tscm cells is relatively low. This means that the inclusion of Tscm cells in the human naive T cell compartment could have resulted in an underestimation of the TREC content, increasing with age due to an expanding Tscm cell population. Hence, in this project, the TREC content of human truly naive T cells was quantified. Even with exclusion of Tscm cells, a similar decline in TREC content of truly naive T cells was observed, indicating that the human naive T cell compartment is truly maintained by peripheral division. It also appears that the thymus is more involved in the production of human CD8+ than CD4+ truly naive T cells.

In contrast to humans, the naive T cell pool in specific pathogen-free (SPF) mice is mostly maintained through thymic output. As it has been suggested that the level of pathogen exposure can directly influence naive T cell dynamics, the TREC content of naive T cells from wildlings, a special mouse model which immune phenotype is more similar to that of humans, was also quantified. Between the age of ten to twenty-nine weeks, the TREC content of naive T cells from wildlings remained relatively constant. These results indicate that the naive T cell pool in wildlings is, just like in SPF mice, mostly produced by the thymus.

All these findings together show that the maintenance of naive T cells during homeostasis is differently regulated in mice and men. Where the human truly naive T cell compartment appears to be mainly maintained through peripheral division, naive T cells in mice are mostly produced by the thymus. Using the mouse as a direct model for humans should therefore be done with caution. Further study is required to explore what could explain this difference in naive T cell maintenance.