Tumor necrosis factor superfamily in innate immunity and inflammation

Abstract

The tumor necrosis factor superfamily (TNFSF) and its corresponding receptor superfamily (TNFRSF) form communication pathways required for developmental, homeostatic, and stimulus-responsive processes in vivo. Although this receptor-ligand system operates between many different cell types and organ systems, many of these proteins play specific roles in immune system function. The TNFSF and TNFRSF proteins lymphotoxins, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator [HVEM], a receptor expressed by T lymphocytes), lymphotoxin-β receptor (LT-βR), and HVEM are used by embryonic and adult innate lymphocytes to promote the development and homeostasis of lymphoid organs. Lymphotoxin-expressing innate-acting B cells construct microenvironments in lymphoid organs that restrict pathogen spread and initiate interferon defenses. Recent results illustrate how the communication networks formed among these cytokines and the coreceptors B and T lymphocyte attenuator (BTLA) and CD160 both inhibit and activate innate lymphoid cells (ILCs), innate γδ T cells, and natural killer (NK) cells. Understanding the role of TNFSF/TNFRSF and interacting proteins in innate cells will likely reveal avenues for future therapeutics for human disease.

Figure 1.

The lymphotoxin LIGHT-related network. The diagram depicts the binding interactions between cytokines and receptors related to lymphotoxins. The arrows define the specificity of the ligand–receptor interactions. Arrowheads define the directionality of signaling, with dual arrowheads defining bidirectional signaling. The TNF-related ligands include TNF-α, LT-α, LT-α1β2, and LIGHT (TNFSF14) and are shown as trimers in their membrane-bound form and expressed in lymphoid cells. Their cognate receptors, TNFRI, TNFRII, LT-βR, and HVEM (TNFRSF14), are expressed in stromal and myeloid cells. Decoy receptor-3 is secreted and also binds Fas ligand and TL1A (TNFSF25) (not shown). HVEM binds the Ig superfamily members BTLA and CD160, which form bidirectional-signaling pathways. BTLA and HVEM are coexpressed in lymphocytes forming a complex in cis. Not shown in this diagram are herpesvirus proteins gD and UL144 that signal via HVEM or BTLA. DcR3, decoy receptor 3. (From Bjordahl et al. 2013; reprinted, with permission, from Elsevier © 2013.)

Figure 2.

TNFRSF proteins associated with innate cells. Groups 1, 2, and 3 ILC, γδ T cells, and NK cells are displayed showing the transcription factors required for specific differentiation of each innate lineage (within the cell). Differentiation of ILC and γδ T cells is discussed within the text. NK cell differentiation has been shown to depend on a number of factors including both the T-box factors T-bet and Eomes, the basic leucine zipper factor E4BP4, and the E protein repressor Id2 for maintenance of mature NK cells (Boos et al. 2007; Gascoyne et al. 2009; Kamizono et al. 2009; Gordon et al. 2012). Cytokine production and effector function are displayed directly below the cells, and the TNFRSF and TNFSF proteins discussed are shown at the bottom.

Figure 3.

Innate B cells and sentinel pathogen permissive cells. Innate B cells in lymphoid organs express the LT-αβ that specifically engages the LT-βR expressed in lymphoid tissue stromal cells and myeloid lineage cells including marginal sinus macrophages. LT-αβ signals differentiate stromal cells macrophages into sentinel IFN-I producing cells and allow virus production. The B cell to stromal cell interaction creates microenvironments of lymphocytes through secretion of chemokines and IL-7. CMV infects stromal cells in the splenic marginal sinus from which IFN-I is rapidly expressed and secreted. B-cell expression of LT-αβ is also required for the differentiation and recruitment of Siglec1-expressing macrophages in lymph organs. Usp18 creates a permissive state for virus replication in macrophages. Vesicular stomatitis virus (VSV) infects macrophages inducing production of IFN-I. Virus replication and progeny are produced (red arrows) in the permissive stromal cells or CD169⁺ macrophages. IFN-αβ protects uninfected cells in the surrounding microenvironment. High virus production allows antigen-specific B cells to capture antigen, migrate, and engage T follicular helper (T_FH) cells for antibody production. Mac, macrophage.

Figure 4.

Dual regulation of NK-cell activation by CD160 and BTLA. (1) NK cells are activated by NK receptors (e.g., NKG2D), and cytokine receptors (e.g., IL-2, type I interferon), to signal through the ERK and Akt pathways; (2) CD160 costimulates ERK and Akt activation, enhancing NK cell effector function; and (3) BTLA inhibits NK-cell activation resulting in reduced target cell lysis.

Figure 5.

BTLA regulation of IL-7 responses in γδ T cells. (1) IL-7 binding to IL-7 receptor activates JAK1 inducing STAT3 and STAT5 activation and nuclear localization; (2) IL-7 signaling in part drives homeostatic proliferation of γδ T cells (and ILC), IL-17 and TNF-α expression in CD27⁻ γδ T cells, and increased levels of surface BTLA in γδ T cells (and ILC); and (3) BTLA expression inhibits IL-7 responses in γδ T cells.