What are they? Lymphoid tissue inducer (LTi) cells are a hematopoietic cell type with critical roles in the immune system during both the embryonic and adult stages of development. Their distinguishing features are expression of RORγt and IL-7Rα in the absence of lineage markers (e.g. CD3, CD19, B220, CD11c, Gr-1). CD4 expression is something of a red herring (despite aiding identification), since both CD4+ and CD4− LTi cells exist in mice, whilst in humans they all appear to be CD4−. Constitutive expression of OX40L is another good marker for LTi cells in the adult (in mice and humans) (Figure 1Figure 1).Figure 1A selection of molecules expressed by LTi cells in the embryo and adult that appear critical for the described functions of these cells.Molecules expressed by LTi cells in both the embryo and adult are shown in yellow and those expressed only in the adult are shown in orange. Lymphotoxin α1β2 (LTα1β2), RANKL, OX40L and CD30L are TNF superfamily members, and CXCR5, CCR7, CCR6 and CXCR6 are chemokine receptors. IL-22, interleukin-22; IL-7Rα, interleukin-7 receptor α.View Large Image | View Hi-Res Image | Download PowerPoint SlideAlso known as… Although these cells were initially termed CD45+CD4+CD3− cells, on the basis of the expression of these surface markers, they were named LTi cells following the recognition of their key role in the development of lymph nodes and Peyer's patches. Recently these cells have been included in the growing list of innate lymphoid cells (ILCs).When did they first come to prominence? Although identified as one of the first cells to colonise the developing lymph node anlagen, the demonstration that these cells (and secondary lymphoid tissue) were dependent upon expression of the orphan transcription factor RORγt really brought LTi cells to the immunological foreground with RORγ−/− mice providing an in vivo means of testing their function. The shared expression of RORγt by Th17 cells also sparked interest in LTi cells.When were they in their heyday? Now! Based on the almost monthly appearances of LTi cells in papers in top journals, it appears that a good proportion of the iceberg is within sight.Not to be confused with… A host of recent papers have identified RORγt-dependent cells that (to varying degrees) are phenotypically distinct from LTi cells. These cells have only been identified within the adult, and LTi cells appear to be the only (non-T-cell) RORγt-expressing population in the embryo. Notably, cells with a phenotype near identical to LTi cells, but also expressing natural killer cell markers, have been reported within the small intestine. Given that these cells have not been detected in the embryo, they do not appear to be involved in secondary lymphoid tissue formation. The lineage relationships between these populations is currently being debated.Bone of contention… Given their name, implicitly implied in their function is the ability to induce formation of secondary lymphoid tissue. Whilst LTi cells persist after birth, it is technically very difficult to demonstrate that these cells are still able to induce the formation of secondary lymphoid tissue, although it has been shown that they can induce Peyer's patch formation in neonatal mice lacking these structures. Therefore, there is some concern that the continued use of the name LTi cell, when describing these cells in the adult, may be misleading.What was their earliest known function? LTi cells are clearly required for the formation of lymph nodes and Peyer's patches — but interestingly not for the formation of organised splenic white pulp — through the provision of the tumour necrosis factor (TNF) superfamily ligands lymphotoxin α1β2 and RANKL. These cells also induce the expression of the autoimmune regulator (AIRE) gene by medullary thymic epithelial cells in the developing embryonic thymus through provision of RANKL signals. Therefore, LTi cells in the embryo are the critical providers of both lymphotoxin α1β2 and RANKL signals, before lymphocyte populations have reached the periphery.And their newly identified functions? Because the formation of secondary lymphoid tissue is restricted to a specific window of embryonic development, whether the LTi cells identified in the adult had acquired additional functions became of great interest. A number of studies using RORγt-deficient mice have implicated LTi cells in the recovery of splenic architecture after viral infection, T-cell-independent immunoglobulin A switching in the gut, and enhanced tumour rejection. Furthermore, much work has focused on the production of the interleukins IL-22 and IL-17 by LTi (and LTi-like) cells within the gut. The function of LTi cells in the embryo centres around their expression of the TNF superfamily members at a critical time and place. Interestingly, after birth LTi cells constitutively express high levels of two other TNF superfamily members — OX40L and CD30L — and become critical providers of these signals to memory CD4+ T cells. The formation of lymph nodes and the ability to generate memory immune responses co-evolved only within placental mammals. Therefore, LTi cells not only orchestrate the formation of lymph nodes, but they also enable the survival of memory CD4+ T cells within these structures.Most outrageous claim… A few years ago most of the current ideas about function would have been dismissed out of hand so perhaps we should wait a while longer before ruling anything out….What are their known associates? Stromal cells in both lymphoid tissue development and perhaps resistance to tumours. Beyond that, interactions with nearly every hematopoietic cell imaginable have been suggested.Obvious question we still don't know the answer to… Given the similarities between the development of secondary lymphoid tissue and the formation of organised lymphoid aggregates during chronic inflammations, a role for LTi cells in the establishment of tertiary lymphoid tissue is suspected but as yet unproven.Any therapeutic potential? The role of LTi cells (and OX40L/CD30L) in the survival of memory CD4+ T cells has significant implications for improving desired memory responses after vaccination as well as in the potential elimination of autoreactive cells.