Emerging immune functions of non-hematopoietic stromal cells

The proper function of the immune system is dependent on interactions between haematopoietic cells and non-hematopoietic stromal cells, which comprise the ensemble of tissue-forming cells (fibroblasts, endothelial cells, nerve cells etc.) that form the microenvironments in which immune responses occur. This collection of cells is also referred to as the immune stroma. It creates a microenvironment in which the immune system operates, providing an architectural landscape for hematopoietic cell-cell interactions and molecular cues governing haematopoietic cell positioning, growth and survival. It is the organisation of stromal cell networks that imposes order on adaptive and innate immune cells and thus drives efficient immune responses. This interdependence of stromal cells of different lineages with all types of hematopoietic cells is therefore an integral part of primary (bone marrow, thymus), secondary (lymph nodes, mucosal-associated lymphoid tissue) and tertiary lymphoid tissue (that arise in response to chronic inflammation). Even in healthy tissue the type of stroma and its cellular activity influences its hematopoietic composition and may determine whether or not tertiary lymphoid structures form in case of unresolved inflammation, characteristic of many infectious, autoimmune, haematological malignancies and inflammatory diseases. One of the earliest motives that have fuelled the study of immune stroma has been the interest in immune system development and the quest to define the action of a set of molecules required for primary and secondary lymphoid organ formation. Some effects were radical leading to a total absence or lymphoid organs whereas some were mild resulting in the reduction of a subset of hematopoietic cells such as B cells owing to the absence of follicular dendritic cells. These early works have also laid one of the principle distinction between stroma and hematopoietic cells, namely the relative radioresistance of stroma. This observation has been fundamental to many experimental analyses aimed at deciphering the molecular makeup of stroma leading for instance to the discovery of lymphotoxin-sensitive stroma. This approach is now being displaced by the advent of mouse models allowing stroma and haematopoietic specific gene deletion and reporter gene expression. In addition, the development of techniques to analyse stroma by flow cytometry together with high resolution 4Dimensional microscopic techniques have helped to loosen the knot that has hampered fast-track discovery science. The study of immune stroma and its interaction