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 in bone-marrow and lymphoid and non-lymphoid tissues. We will use a combination of in vivo stable-isotope labelling, 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 laboratory mice exposed to feral mice, because their memory T-cell pools are much more representative of the human immune system than those of clean laboratory mice.