Ectopic lymphoid follicles: inducible centres for generating antigen-specific immune responses within tissues

Abstract

Lymphoid neogenesis is traditionally viewed as a pre-programmed process that promotes the formation of lymphoid organs during development. Here, the spatial organization of T and B cells in lymph nodes and spleen into discrete structures regulates antigen-specific responses and adaptive immunity following immune challenge. However, lymphoid neogenesis is also triggered by chronic or persistent inflammation. Here, ectopic (or tertiary) lymphoid organs frequently develop in inflamed tissues as a response to infection, auto-immunity, transplantation, cancer or environmental irritants. Although these structures affect local immune responses, the contribution of these lymphoid aggregates to the underlining pathology are highly context dependent and can elicit either protective or deleterious outcomes. Here we review the cellular and molecular mechanisms responsible for ectopic lymphoid neogenesis and consider the relevance of these structures in human disease.

Keywords: arthritis; autoimmunity; cancer; infection; lymphoid neogenesis.

Figure 1

Novel immune cell subsets implicated in the regulation of ectopic lymphoid follicles (ELFs). Novel innate and adaptive immune cell subsets have recently been implicated in ELF regulation. These include the adult lymphoid tissue inducer (LTi) ‐like or innate lymphoid 3 cells, interleukin‐17 (IL‐17) ‐producing γδT (Tγδ17) cells, T helper type 17 (Th17) cells and follicular T helper (Tfh) cells. Here we highlight the similarities in their phenotype including the cytokines involved in their development, proliferation and effector function, the receptors expressed on the cell surface and the effector cytokines produced by these cells. Similarities in the effector characteristics of these cells may account for their common ability to regulate ELF development or activity. TSLP, thymic stromal lymphopoietin; SCF, stem cell factor; GM‐CSF, granulocyte–macrophage colony‐stimulating factor; TNF, tumour necrosis factor; PD‐1, programmed cell death‐1; ICOS, inducible T‐cell co‐stimulator.

Figure 2

Novel cytokine regulators of ectopic lymphoid follicle (ELF) development and function. The formation of ELFs at sites of chronic inflammation mirrors the pre‐programmed development of conventional secondary lymphoid organs (SLOs). During secondary lymphoid organogenesis, the cytokines interleukin‐7 (IL‐7), receptor activator of nuclear factor‐κB ligand (RANKL) and lymphotoxin (LT) αβ initiate the chemokine‐directed positive feedback loop that drives B‐cell, T‐cell and follicular dendritic cell (DC) recruitment during lymphoid neogenesis. Recent studies have implicated novel T helper cell subsets as initiators of ELF formation. Given the role that cytokines play in the regulation of T helper cell differentiation and effector function, a number of cytokines have now been linked with the control of ELFs. For example, cytokines involved in the regulation of T helper type 17 (Th17) cell responses (IL‐6, IL‐21, IL‐23, IL‐27, IL‐2, IL‐22, IL‐17)23, 137, 139, 145, 148, 152 and follicular T helper (Tfh) cell responses [IL‐6, IL‐21, Type I interferons (IFNs), IL‐27, IL‐2]137, 139, 146, 147, 150 are emerging as regulators of lymphoid neogenesis. Here we highlight cytokines that may positively (red) and negatively (blue) control ELFs based on their ability to regulate effector T‐cell populations involved in ELF development or function. These cytokines, as well as their downstream signalling pathways and transcription factors, have the potential to serve as therapeutic targets in clinical conditions where ELFs feature.