Leslie Summers deLuca

Fine-tuning of dendritic cell biology by the TNF superfamily

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.

LTβR signaling in dendritic cells induces a type I IFN response that is required for optimal clonal expansion of CD8+ T cells

During an immune response, antigen-bearing dendritic cells (DCs) migrate to the local draining lymph node and present antigen to CD4+ helper T cells. Antigen-activated CD4+ T cells then up-regulate TNF superfamily members including CD40 ligand and lymphotoxin (LT)αβ. Although it is well-accepted that CD40 stimulation on DCs is required for DC licensing and cross-priming of CD8+ T-cell responses, it is likely that other signals are integrated into a comprehensive DC activation program. Here we show that a cognate interaction between LTαβ on CD4+ helper T cells and LTβ receptor on DCs results in unique signals that are necessary for optimal CD8+ T-cell expansion via a type I IFN-dependent mechanism. In contrast, CD40 signaling appears to be more critical for CD8+ T-cell IFNγ production. Therefore, different TNF family members provide integrative signals that shape the licensing potential of antigen-presenting DCs.

Substrain Differences Reveal Novel Disease-Modifying Gene Candidates That Alter the Clinical Course of a Rodent Model of Multiple Sclerosis

Experimental autoimmune encephalomyelitis (EAE) is a rodent model of multiple sclerosis that is executed in animals by immunization with myelin Ag in adjuvant. The SJL/J autoimmune-prone strain of mouse has been used to model relapsing–remitting multiple sclerosis. However, significant variations in peak scores, timing of onset, and incidence are observed among laboratories, with the postacute (relapse) phase of the disease exhibiting significant inconsistency. We characterized two substrains of SJL/J mice that exhibit profoundly different EAE disease parameters. Induction of EAE in the first SJL/J substrain resulted in many cases of chronic EAE that was dominated by an aggressive B cell response to the immunizing Ag and to endogenous CNS Ags. In contrast, the other SJL/J substrain exhibited a relapsing–remitting form of EAE concomitant with an elevated number of cytokine-producing CD4+ T cells in the CNS. Exploiting these interstrain differences, we performed a genome-wide copy number analysis on the two disparate SJL/J substrains and discovered numerous gene-dosage differences. In particular, one inflammation-associated gene, Naip1, was present at a higher copy number in the SJL/J substrain that exhibited relapsing–remitting EAE. These results demonstrate that substrain differences, perhaps at the level of genomic copy number, can account for variability in the postacute phase of EAE and may drive chronic versus relapsing disease.

LTβR and CD40: working together in dendritic cells to optimize immune responses

Summary:  Generating an immune response tailored to destroy an infecting organism while limiting bystander damage involves guiding T‐cell activation using a variety of cues taken from the immunogen (antigen type, dose, and persistence, accompanying danger signals) as well as the host (tissue environment, T‐cell frequency, and affinity for antigen). Dendritic cells (DCs) serve as translators of much of this information and are critically required for effective pathogen and tumor clearance. Moreover, dysregulation of DC activation can lead to autoimmunity. Inhibition of the lymphotoxin (LT) and CD40 pathways has been shown to be effective at quieting inflammation in settings where DC–T‐cell interactions are key instigators of disease progression. In this review, we compare and contrast the CD40 and LT pathways in the context of receptor/ligand expression, signal transduction, and DC biology. We provide evidence that these two pathways play complementary roles in DC cytokine secretion, thus indirectly shaping the nature of the CD8+ T‐cell response to foreign antigen. Given the distinct role of these pathways in the context of DC function, we propose that dual therapies targeted at both the CD40 and LTβ receptor may have therapeutic potential in silencing DC‐driven autoimmunity or in promoting tumor clearance.

A TNF-α–CCL20–CCR6 Axis Regulates Nod1-Induced B Cell Responses

Innate immune responses provoke the accumulation of leukocytes at sites of inflammation. In addition to monocytes and granulocytes, B cells also participate in antimicrobial innate immune responses; however, the mechanisms for accumulation of B cells to sites of inflammation are not well understood. To study B cell accumulation following systemic inflammation, we used a model synthetic ligand that stimulates a specific pattern recognition molecule, nucleotide-binding oligomerization domain–containing protein 1 (Nod1). Upon exposure to Nod1 agonists, both B cells and neutrophils rapidly accumulate within the spleen, and dendritic cells migrate into the periarterial lymphoid sheath. Nod1 stimulation led to a marked increase in several chemokines within the spleen, including CXCL13, CCL2, and CCL20. Whereas the lymphotoxin pathway was critical for the induction of the B cell chemoattractant CXCL13 in response to Nod1 agonists, B cell accumulation within the spleen following Nod1-induced systemic inflammation was independent of the lymphotoxin pathway. In contrast, a CCR6/CCL20 chemokine loop instructed rapid increase of B cells in the spleen in response to systemic administration of Nod1 agonists in a TNF-α–dependent manner. Moreover, CCR6 was required to regulate Nod1-mediated B cell responses. These results reveal a novel mechanism of B cells during inflammation and shed light on how B cells participate in innate immune responses to microbial stimulation.

The lymphotoxin pathway as a novel regulator of dendritic cell function.

Dendritic cells (DC) are critically required for the host response to antigen (Ag) [1, 2]. Upon exposure to antigen, DC take up Ag within the peripheral tissues and subsequently migrate in response to chemokine gradients into the lymphatics [3]. During this initial exposure to Ag, DC become activated by the sensing of microbe-associated molecular patterns (MAMPs) and consequently upregulate co-stimulatory molecules such as B7.1 and B7.2 so that they may optimally prime Ag-specific CD4+ T cells [4–6]. DC leave the tissue and enter the lymphatics where they journey to the inflamed draining lymph node (LN) [7, 8]. Upon entry into the LN via the subcapsular sinus, DC “find” rare Ag-specific CD4+ T cells by taking advantage of the intricate organization of the LN tissue itself [9]. Once DC encounter Ag-specific T cells, the T cells become activated to proliferate. These activated T cells also concurrently provide signals back to the Ag-bearing DC in a process that has been termed DC licensing. Licensed DC can then cross-prime a CD8+ T-cell response so that pathogen may be cleared. The nature of these helper T cell-derived signals and their impact on the Ag-bearing DC remain poorly elucidated.