Longevity of the adaptive immune cell compartment in the human small intestine

The intestinal immune system must rapidly respond to pathogens while maintaining the tolerance against commensals and dietary antigens. To accomplish this task, the gut contains the largest number of adaptive immune cells in the body, including antibody-producing plasma cells (PCs) and antigen-experienced T cells. The focus of this thesis is to study the homeostatic turnover, phenotype and function of different populations of memory T cells, including CD8+ and CD4+ resident memory T cells (Trm), regulatory T cells (Treg) as well as PCs in the human small intestine. During the last decade, it has been shown that T cell immunosurveillance in peripheral tissues is accomplished for the most part by resident populations (Trm cells) that do not recirculate. In the first study of this thesis we evaluated the turnover of CD8+ T cell subsets in transplanted small intestine and we found that the majority of the CD103+ CD8+ T cells persisted in the graft for one year after transplantation, suggesting that they constitute bona fide Trm cells. In addition, they displayed a TCR repertoire dominated by expanded clones that were conserved over time. In contrast, CD103- CD8+ T cells presented different phenotype, functional capabilities and immune repertoire compared to CD103+ CD8+ T cells. Moreover, CD103- CD8+ T cells were rapidly exchanged after one year, indicating that they constitute recently recruited cells. In the second study we demonstrated that intestinal CD4+ T cell compartment is mainly composed by CD103- and CD103+ resident populations that survive for at least one year in transplanted duodenum and present a polyfunctional Th1 profile. Furthermore, in the third study we revealed that the human small intestine contains two functionally distinct populations of CD4+ Treg cells: a resident subset of Helios- Treg cells and a subset of Helios+ Treg cells that is dynamically exchanged. Finally, we demonstrated that most of the intestinal PCs constitute long-lived cells with a lifespan of several decades and these cells are enriched for specificities against previous infections. Taken together, these results show that the human small intestine harbors very persistent PCs and T cells, which has profound implications for the development of mucosal vaccines and new immunotherapies