The Lymphotoxin Network: orchestrating a type I interferon response to optimize adaptive immunity

Abstract

The Lymphotoxin (LT) pathway is best known for its role in orchestrating the development and homeostasis of lymph nodes and Peyer's patches through the regulation of homeostatic chemokines. More recently an appreciation of the LTβR pathway in the production of Type I interferons (IFN-I) during homeostasis and infection has emerged. LTβR signaling is essential in differentiating stromal cells and macrophages in lymphoid organs to rapidly produce IFN-I in response to virus infections independently of the conventional TLR signaling systems. In addition, LTβR signaling is required to produce homeostatic levels of IFN-I from dendritic cells in order to effectively cross-prime a CD8+ T cell response to protein antigen. Importantly, pharmacological inhibition of LTβR signaling in mice has a profound positive impact on a number of autoimmune disease models, although it remains unclear if this efficacy is linked to IFN-I production during chronic inflammation. In this review, we will provide a brief overview of how the "Lymphotoxin Network" is linked to the IFN-I response and its impact on the immune system.

Keywords: Autoimmunity; Dendritic cells; Interferon (IFN); Lymphotoxin-αβ (LTαβ); Stromal cells.

Figure 1. Innate B cells and Sentinel Pathogen Permissive Cells

In lymphoid organs, stromal cells produce IL-7 that induces LT! ! expression on the surface of B cells. B cells engage LT! R expressing stromal cells and macrophages in marginal sinuses of lymphoid organs promoting their differentiation into sentinel cells that upon virus infection rapidly produce IFN-I. For example, cytomegalovirus (CMV) productively infects splenic stromal cells, which also produce type 1 interferons (IFN-I). In response to vesicular stomatitis virus (VSV), sinus-lining macrophages are productively infected and also produce IFN-I. These sinus-lining macrophages are themselves resistant to the effect of IFN-I via Usp18, an ISG-15 deconjugating enzyme that also blocks IFN Receptor signaling. Consequently these cells are permissive for VSV infection. It is thought that the permissive state of these macrophages provides high antigen production for capture and presentation to the adaptive immune system.

Figure 2. Proposed model of LT! R-dependent dendritic cell licensing during a help-dependent immune response

In settings where CD8⁺ T cell responses are help-dependent (such as immune responses to non-replicating antigen or cell-associated antigen), dendritic cell-intrinsic LT! R signals are important for optimizing local production of IFN-I. This modest amount of IFN-I is required for optimal CD8⁺ T cell clonal expansion. The dendritic cell-intrinsic LT! R signal is not required for CD8⁺ T cell effector function, such as IFN! secretion. Conversely, CD40 signaling in dendritic cells is necessary for CD8+ T cell effector function but dispensable for CD8⁺ T cell clonal expansion.