Lymphotoxin signalling in immune homeostasis and the control of microorganisms

Abstract

Lymphotoxin (LT) is a member of the tumour necrosis factor (TNF) superfamily that was originally thought to be functionally redundant to TNF, but these proteins were later found to have independent roles in driving lymphoid organogenesis. More recently, LT-mediated signalling has been shown to actively contribute to effector immune responses. LT regulates dendritic cell and CD4(+) T cell homeostasis in the steady state and determines the functions of these cells during pathogenic challenges. The LT receptor pathway is essential for controlling pathogens and even contributes to the regulation of the intestinal microbiota, with recent data suggesting that LT-induced changes in the microbiota promote metabolic disease. In this Review, we discuss these newly defined roles for LT, with a particular focus on how the LT receptor pathway regulates innate and adaptive immune responses to microorganisms.

Figure 1. The LT pathway regulates DC fates

Dendritic cells (DCs) require lymphotoxin-α₁β₂ (LTα₁β₂) that is provided by a currently undefined cell type. Endothelial cell selective adhesion molecule (ESAM)^hi splenic DCs, which are essential for priming CD4⁺Tcells, require T signaling for their development^,. In the gut, LTβR induces the maturation of inducible nitric oxide synthase (iNOS)⁺ DCs, which then induce the development of IgA producing plasmablasts. In both of these cases, further studies are required to define the cellular source of the LT. Additionally, in the lymph nodes, DCs have recently been shown to express LTα₁β₂ (REF. 18), which is recognized by high endothelial venules (HEVs) and leads to their upregulation of adhesion molecules, such as glycosylation dependent cell adhesion molecule 1 (GLYCAM1), and is important for maintaining lymph node cellularity in the steady state. ILC, innate lymphoid cell.

Figure 2. LT coordinates adaptive immunity

The lymphotoxin (LT) pathway organizes multicellular interactions in the lymph node. B cell-derived LTα₁β₂ is recognized by the LTβ receptor (LTβR), which is expressed on follicular dendritic cells (FDCs), and this interaction promotes the secretion of chemokines that recruit antigen presenting dendritic cells (DCs) and CD4⁺ T cells to facilitate the development of T helper cell responses^,. In the germinal centre, miR-155 expression in B cells maintains LT expression. Ligation of inducible T cell co-stimulator (ICOS) on T cells to ICOS ligand (ICOSL) on B cells and the CD40–CD40 ligand (CD40L) interaction are also essential for the upregulation of LT on B cells that enables a germinal centre response ^,. CXCL13, CXC chemokine ligand 13; CXCR5, CXC chemokine receptor 5; TCR, T cell receptor.

Figure 3. Regulation of viral infections with LT

In the fully developed host, B cells provide lymphotoxin (LT), which is recognized by the macrophages that populate the subcapsular sinus (SCS) of the lymph node and causes them to adopt an SCS macrophage phenotype (CD11b⁺CD169⁺). These macrophages engulf particulate antigens, including vesicular stomatitis virus (VSV), and prevent their spread to the periphery^,. The macrophages also produce protective type I interferons (IFNs). During lymphocytic choriomeningitis (LCMV) infection, active LT signalling is required to organize B cell follicles; the cell type sensing this LT signalling is currently uncharacterized, but might be the high endothelial venule (HEV) (not shown). The LT pathway is also essential for the production of type I IFNs from radio-resistant cells in the spleen that protect the host during viral infection^, (not shown). In addition, dendritic cells (DCs) that produce type I IFN in response to LTβ receptor (LTβR) agonism and Toll like receptor (TLR) signalling promote CD8⁺ T cell homeostasis in the spleen^, (not shown).

Figure 4. LT regulates responses to microorganisms at mucosal surfaces

a|During Citrobacter rodentium infection, the lymphotoxin (LT) pathway is part of an innate feedback loop in which retinoic acid receptor related orphan receptor γt(RORγt) innate lymphoid cells (ILCs)induce interleukin 12(IL 12) and IL 23production by local dendritic cells (DCs) via the LT pathway^,. In response to IL 23, these ILCs produce IL 22, which promotes gut epithelial cells to produce antimicrobial peptides, such as RegIIIβ and RegIIIγ. These antimicrobial peptides have direct killing functions on C. rodentium and members of the commensal microbiota. LT dependent interactions between ILCs and stromal cells can also support the formation of isolated lymphoid follicles (ILFs) during infections. b | In response to a high fat diet, LT signalling is increased within the colon (V.U. and Y. X.F., unpublished observations) and this increases IL 23 and IL 22 production. This then induces the production of antibacterial proteins, which are essential for the clearance of some microorganisms (such as segmented filamentous bacteria (SFB)) in response to high fat diet administration and which contribute to the alteration of the microbiota, which in turn confers greater weight gain. IL 22R, interleukin 22 receptor; LTβR, LTβ receptor.