Microbiota-Dependent Sequelae of Acute Infection Compromise Tissue-Specific Immunity

Abstract

Summary Infections have been proposed as initiating factors for inflammatory disorders, however, identifying associations between defined infectious agents and the initiation of chronic disease has remained elusive. Here, we report that a single acute infection can have dramatic and long-term consequences for tissue-specific immunity. Following clearance of Yersinia pseudotuberculosis, sustained inflammation and associated lymphatic leakage in the mesenteric adipose tissue deviates migratory dendritic cells to the adipose compartment, thereby preventing their accumulation in the mesenteric lymph node. As a consequence, canonical mucosal immune functions, including tolerance and protective immunity, are persistently compromised. Post-resolution of infection, signals derived from the microbiota maintain inflammatory mesentery remodeling and consequently, transient ablation of the microbiota restores mucosal immunity. Our results indicate that persistent disruption of communication between tissues and the immune system following clearance of an acute infection represents an inflection point beyond which tissue homeostasis and immunity is compromised for the long-term.

Lymphoid Aggregates Remodel Lymphatic Collecting Vessels that Serve Mesenteric Lymph Nodes in Crohn Disease

“…Given that two different mouse models have linked chronic inflammatory changes in the intestine to failed dendritic cell migration to lymph nodes, 2,3 it is especially compelling to consider that the TLOs may alter dendritic cell access to draining lymph nodes.…”

“…3 In the case of infectioninduced impairment of dendritic cell migration, the inhibition was apparently caused by compromised lymphatic integrity that damaged lymphatic collecting vessels in the mesentery and left them highly hyperpermeable, such that the contents of lymph spilled out into the mesentery, including migratory dendritic cells, rather than progressing to downstream mesenteric LNs. 2 An interesting consideration that results from this work is whether related phenomena might contribute to inflammatory bowel disease in humans. Indeed, lymphatic dysfunction has been long discussed, although often overlooked, in Crohn disease (CD).…”

“…1 A recent study that followed mice for weeks after Yersinia pseudotuberculosis infection revealed that long after the infection was completely cleared, immune dysregulation persisted. 2 This persistence was because of tissue insult that lingered and continuously deviated the immune response, normally programmed in draining lymph nodes (LNs), in part by inhibiting dendritic cell trafficking to the LNs. Inhibition of dendritic cell trafficking to LNs has also been found to underlie ileitis in the SAMP1/YitFc mouse model.…”

CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability

“…In contrast, YFP + DCs visualized in the Ccr7 -/-backunder exceptional circumstances do these lymphatic-associated, adipose tissue DCs mobilize to LNs (14), so the reason why they constitutively interact with the lymphatic collecting vessel and monitor the filtrate from this vessel has been unclear. Recently, extremely permeable lymphatic collecting vessels were identified as a consequence of aberrant healing following infection with Yersinia pestis (15). These collecting vessels became leaky enough to prevent the arrival of migratory DCs in draining mesenteric LNs.…”

Multiplex, quantitative cellular analysis in large tissue volumes with clearing-enhanced 3D microscopy (C e 3D)

“…This imaging/analysis pipeline allows multiplex phenotypic identification and quantification of cells directly in tissues, akin to in situ flow cytometry. This technique has been used to study the composition, distribution, and function of densely packed cells with complex phenotypes and morphology in tissue sections (13)(14)(15)(16)(17)(18)(19)(20)(21). Even for cell types with relatively simple morphology, such as T and B lymphocytes, histo-cytometry requires a high degree of spatial signal resolution, achieved with high numerical aperture (N.A.)…”