Quantification of memory T-cell dynamics

Elena de Dios Panal

Immunological memory is one of the hallmarks of the adaptive immune system. Because T-cell memory typically lasts for decades, memory T-cells are often thought to be long-lived cells. There is compelling evidence that this is a too simplified view. We have shown that human blood-derived memory T-cells live on average 160 days, much shorter than the immunological memory they convey. Recent studies have shown, however, that the most protective memory T-cells reside in bone-marrow and non-lymphoid tissues, and hence go unnoticed in most immunological studies, based on blood or lymphoid tissues. Extremely little is known about the maintenance of these bone-marrow and tissue-resident T-cells, whether they are maintained by self-renewal, by cellular longevity, or by input from other memory subsets.

We will study the fundamental basis of long-term T-cell memory by quantifying the in-vivo dynamics and T-cell repertoire composition of different memory T-cell subsets. We will use a combination of in-vivo stable-isotope labeling, barcoded next-generation sequencing and mathematical modelling to develop an integrated, total-body model for long-term maintenance of T-cell memory. The experiments will be performed in health and disease, in humans as well as in mice.

In order to study the T cell receptor (TCR) repertoire composition of different memory T cell populations, memory T cells will be sorted from the blood of healthy humans and the blood and bone marrow of patients undergoing an elective hip replacement. To estimate the average proliferation and death rates of these different memory T cell populations in vivo, deuterated water will be administered to both groups.

Inspired by Beura et al., who showed in 2016, that cohousing of SPF C57BL/6 mice with “dirty” pet store mice shifts the T-cell memory pool of SPF laboratory mice from an immature human like to an adult human like T-cell memory, with memory T-cells only being present in dirty circumstances. Hence, we will study particularly the lifespan of tissue-resident memory T-cells by deuterium labeling in C57BL/6 mice exposed to a “dirty” environment, with a higher load of pathogens. In contrast to Beura et al. we will avoid inducing an epidemic outbreak and rather choose to introduce pathogens by natural enrichments such as nesting material of “dirty” mice and soils. This way we hope to introduce a more relevant animal model for the human adaptive immune system while enhancing the housing conditions of laboratory mice.

Thanks to the interdisciplinary nature of our research group, in which mathematicians and experimental immunologists collaborate on a daily basis, we are in the unique position to generate these insights into this largely unexplored part of the immune system by a bilateral approach.

In a parallel study we will investigate the dynamics of different memory T-cell populations in HIV patients on long-term cART. Presence of a stable reservoir of HIV-infected cells prevents eradication with contemporary treatment strategies. Targeting and eliminating these cells is essential for eradication, yet many basic questions about the leukocyte dynamics in cART treatment remain unanswered. It remains unclear which cell populations contain most of the latent viral reservoir, let alone about their dynamics. We will quantify those dynamics by deuterium labeling and compare them to those of healthy controls.