TRECing down the source: naive and memory T cell generation in dirty mice and men

Abstract

Abstract Healthy aging relies on the maintenance of a diverse T cell pool. This diversity is ensured by balancing thymic output, differentiation of naive into memory T cells, T cell proliferation and cell death. For naive T cells, the balance of these processes differs between standard laboratory mice and humans. This may be a true species difference or, alternatively, result from the vastly different amounts of antigens to which standard laboratory mice and humans are exposed. Using wildlings, that is, laboratory mice born to wild mice, we studied the impact of antigen-exposure through a natural microbiome on naive and memory T cell maintenance. We found that standard laboratory mice and wildlings maintain their naive T cell pools similarly: naive T cells rarely divide and are replaced by thymic emigrants at similar rates. The daily replacement rate of memory T cells, on the other hand, is about 50% faster in wildlings than in standard laboratory mice. In both types of mice, about 20% of newly produced memory T cells originate from recruitment of naive T cells, while the remaining cells are produced by their clonal expansion and by self-renewal. In older mice, this drops to 5%. In humans, a similarly large fraction of memory cells originate from recruitment of naive T cells. Unlike in mice, most naive T cells in human adults are formed by naive T cell proliferation. Thus, while both types of mice mimic the maintenance mechanisms of the memory T cell pool in humans, even wildlings fall short as a model for human naive T cell maintenance.