Inducers & Organizers in Human Fetal and Adult Lymphoid Tissues

Abstract

The human immune system harbors the potential to generate novel lymphoid organs within inflamed tissues during disease. These tertiary lymphoid organs (TLOs) resemble lymph nodes and can contain segregated T and B cell areas, germinal centers, high endothelial venules and follicular dendritic cells (FDCs). While TLO formation is likely to have evolved as a means to locally create an optimal environment for local eradication of infections, evidence is culminating that during chronic or auto-immune inflammation TLOs contribute to sustaining aberrant inflammation, and serve as a site for activation of auto reactive lymphocytes. TLO-like structures can also contribute to the survival of malignancies, since disseminated follicular lymphoma in the bone marrow induces TLO-like structures to acquire a survival supportive microenvironment5,6. In animal models, the development of TLOs with a higher degree of cellular organization, i.e. the segregation of T and B cells and the formation of B cell follicles, is guided by mechanisms similar to those guiding formation of murine lymph nodes during embryogenesis. A crucial event in organized TLO formation is lymphotoxin-β-receptor (LTbR)-dependent initiation of homeostatic chemokine production9. TLO formation is preceded by the accumulation of activated lymphocytes, a process guided by inflammatory chemokines. These chemokines will in most cases be produced by activated cells of the innate immune system10. Subsequently, two criteria are thought to be needed for TLO development. First, expression of the LTbR on tissue-resident stromal or reticulum cells and second, a persistent stimulus such as an auto antigen to ensure the prolonged influx of activated, lymphotoxin-expressing lymphocytes. The subsequently achieved continuous signaling via the LTbR will lead to a switch in chemokine production, in which homeostatic chemokines will eventually be favored over the inflammatory chemokines mainly produced during the initial acute phase of the response9. Eventually, this will result in the influx of naïve lymphocytes and organization into T and B cell areas.