TNF superfamily members have diverse functions in mammalian biology and are often expressed by cells of the immune system. TNF superfamily members are important therapeutic targets for the treatment of autoimmune disease and for encouraging tumour clearance.
Dendritic cells (DCs) are the most potent antigen-presenting cells in the immune system. DC-intrinsic signals can dictate whether T cells respond or show tolerance to an antigen.
The expression of TNF superfamily receptors and ligands by T cells and DCs suggests an important role for this molecular superfamily in T cell–DC crosstalk. TNF superfamily receptors on T cells can provide co-stimulation for the T cell response when they interact with their corresponding TNF superfamily ligands that have been upregulated on DCs.
TNF superfamily receptors that are expressed directly on DCs can provide homeostatic signals to the DCs in the steady state and can function to 'license' the DCs during an immune response by virtue of T cell–DC crosstalk. Licensed DCs secrete pro-inflammatory cytokines and express CD70.
Modulation of TNF superfamily receptor-derived signals in the gut can have a dramatic impact on mucosal inflammation and responses to mucosal pathogens. In the gut, T cell–DC crosstalk may be replaced by communication between DCs and innate lymphoid cells to provoke protective immunity and to maintain tolerance to the resident microbial communities in this location.
Members of the tumour necrosis factor (TNF) superfamily have been implicated in a wide range of biological functions, and their expression by cells of the immune system makes them appealing targets for immunomodulation. One common theme for TNF superfamily members is their coordinated expression at the interface between antigen-specific T cells and antigen-presenting dendritic cells and, by virtue of this expression pattern, TNF superfamily members can shape T cell immune responses. Understanding how to manipulate such functions of the TNF superfamily may allow us to tip the balance between immunity and tolerance in the context of human disease.
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Funding for the research on how the lymphotoxin pathway supports T cell–DC crosstalk was provided by the Canadian Institutes of Health Research (MOP 67157). The authors wish to acknowledge D. Ng, L. Snell and O. Rojas for critical reading of the manuscript.
The authors declare no competing financial interests.
- Dendritic cell
(DC). A potent antigen-presenting cell that acts as a sentinel of the immune system. Located throughout peripheral tissues as well as in the lymphoid tissues of the periphery and the mucosae, these cells acquire and process antigens and present them to rare, antigen-specific T cells.
- TNF superfamily receptors
A molecular superfamily of receptors that trigger signalling events in a wide range of cell types, including cells of the immune system, such as T cells and DCs. Some TNF superfamily receptors (such as TNFR1) can activate cell death (in addition to other functions), whereas others (such as LTβR) can promote cell survival and inflammation.
- Secondary lymphoid organs
Highly organized anatomical structures, including the spleen and peripheral lymph nodes as well as the Peyer's patches and mucosa-associated lymphoid tissues (such as isolated lymphoid follicles and nasopharynx-associated lymphoid tissue). The cellular compartmentalization within these structures is actively maintained by constitutive LTβR signalling.
- Lymphoid-tissue inducer cells
A population of cells that is present in developing lymph nodes, Peyer's patches and nasopharynx-associated lymphoid tissue. Lymphoid-tissue inducer cells are required for the development of these lymphoid organs, and this function is mediated by their interactions with lymphoid-tissue organizer cells.
- Subcapsular sinus macrophages
Specialized macrophages that reside in the subcapsular sinuses of lymph nodes and are efficient at capturing antigens from the lymph.
- Microfold cells
Specialized antigen-sampling cells that are located in the follicle-associated epithelium of the organized mucosa-associated lymphoid tissues. Microfold cells deliver antigens by transepithelial vesicular transport from the aerodigestive lumen directly to subepithelial lymphoid tissues of the nasopharynx-associated lymphoid tissue and Peyer's patches.
- Tertiary lymphoid structures
(Also known as follicle-like structures). Collections of lymphocytes that occur in the context of pathogen-driven or autoimmune inflammation. The organization of such structures varies: some are clusters of lymphocytes and DCs, whereas others have ongoing germinal centre reactions. The organization of such structures is maintained by constitutive LTβR signalling, although the cellular source of LTαβ can vary.
- DC licensing
A concept that a DC must be converted to a functional state by an antigen-specific T helper cell in order to activate cytotoxic CD8+ T cells. T helper cells license DCs by expressing co-stimulatory molecules (such as the TNF superfamily ligands CD40L and LTαβ) or producing cytokines (such as IFNγ).
- Inducible co-stimulatory TNF superfamily receptors
Co-stimulation of the T cell response involves the integration of many signals, including those induced by the engagement of CD28 and other T cell-associated TNF superfamily receptors. T cell-expressed TNF superfamily receptors are typically upregulated in response to T cell receptor activation (hence the term 'inducible co-stimulators'). Likewise, the ligands for these inducible co-stimulators are TNF superfamily members, many of which are upregulated by activated DCs.
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deLuca, L., Gommerman, J. Fine-tuning of dendritic cell biology by the TNF superfamily. Nat Rev Immunol 12, 339–351 (2012). https://doi.org/10.1038/nri3193
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