Novel approaches for immune reconstitution and adaptive immune modeling with human pluripotent stem cells

Pluripotent stem cells have the capacity to generate all cell lineages, and substantial progress has been made in realizing this potential. One fascinating but as yet unrealized possibility is the differentiation of pluripotent stem cells into thymic epithelial cells. The thymus is a primary lymphoid organ essential for naïve T-cell generation. T cells play an important role in adaptive immunity, and their loss or dysfunction underlies in a wide range of autoimmune and infectious diseases. T cells are generated and selected through interaction with thymic epithelial cells, the functionally essential element of thymus. The ability to generate functional thymic epithelial cells from pluripotent stem cells would have applications in modeling human immune responses in mice, in tissue transplantation, and in modulating autoimmune and infectious disease

Thymic maturation and programmed cell death

The thymus plays a crucial role in the development and maintenance of the immune system, being the main site of T cell differentiation and maturation throughout life. Associated to dramatic structural changes, its function seems to markedly diminish with time, never the less, there are several data indicating that, despite organ atrophy, at least part of the thymus remains active throughout one's lifetime. In the last decades, several studies, aiming to understand the significance of age-dependent changes in thymic structure and function, highlighted the concept that developmental and maturational stages strongly depend on the balanced and coordinated occurrence of life and death options. In particular, programmed cell death represents a fundamental requirement in order to assure a proper functionality of the immune response and to avoid the formation of uncontrolled and potentially self-damaging lymphocytic clones. By contrast, the time-dependent thymic atrophy is due to progressive replacing of lymphoid with adipose tissue. In the light of the increased knowledge on the factors/mechanisms controlling the process of adipogenesis, it could be suggested that fat accumulation in the thymic stroma might not be considered a passive, deleterious consequence of aging, but instead a potential source of molecules with various biological functions. Therefore, thymus represents a very interesting model in terms of energy expenditure and trade off, tissue homeostasis, immune defence and disease escape. The implications of changes in thymic structure, in the ratio of proliferation and programmed cell death as well as the occurrence of fat involution still represent an open question and will be discussed in the present chapter