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. 2013 Mar 1;7(2):157–163. doi: 10.4161/pri.23536

Prions and lymphoid organs

Solved and remaining mysteries

Tracy O’Connor 1,*, Adriano Aguzzi 1,*
PMCID: PMC3609124  PMID: 23357827

Abstract

Prion colonization of secondary lymphoid organs (SLOs) is a critical step preceding neuroinvasion in prion pathogenesis. Follicular dendritic cells (FDCs), which depend on both tumor necrosis factor receptor 1 (TNFR1) and lymphotoxin β receptor (LTβR) signaling for maintenance, are thought to be the primary sites of prion accumulation in SLOs. However, prion titers in RML-infected TNFR1−/− lymph nodes and rates of neuroinvasion in TNFR1−/− mice remain high despite the absence of mature FDCs. Recently, we discovered that TNFR1-independent prion accumulation in lymph nodes relies on LTβR signaling. Loss of LTβR signaling in TNFR1−/− lymph nodes coincided with the de-differentiation of high endothelial venules (HEVs)—the primary sites of lymphocyte entry into lymph nodes. These findings suggest that HEVs are the sites through which prions initially invade lymph nodes from the bloodstream. Identification of HEVs as entry portals for prions clarifies a number of previous observations concerning peripheral prion pathogenesis. However, a number of questions still remain: What is the mechanism by which prions are taken up by HEVs? Which cells are responsible for delivering prions to lymph nodes? Are HEVs the main entry site for prions into lymph nodes or do alternative routes also exist? These questions and others are considered in this article.

Keywords: prions, lymph nodes, high endothelial venules, lymphotoxin beta receptor, tumor necrosis factor receptor 1, peripheral prion replication, neuroinvasion, follicular dendritic cell

Introduction

Prions have captured widespread medical interest mainly because of their ability to selectively decimate neurons of the central nervous system (CNS). However, neurological decline is often preceded by prion and PrPSc accumulation in secondary lymphoid organs (SLOs) such as spleen and lymph nodes after peripheral exposure to prions.1-8 This amplification step in SLOs is crucial to the progression of prion pathogenesis, as it is from these sites that prions transmigrate to the peripheral nervous system (PNS) and finally the CNS9-11 in a process known as neuroinvasion. Extraneural prion accumulation is thought to occur primarily within stromal cells found in germinal centers of lymphoid follicles known as follicular dendritic cells (FDCs).2,12-17 Maintenance of mature FDC networks, and hence ability of FDCs to harbor prions, critically depends on continuous signaling through FDC-expressed lymphotoxin β receptor (LTβR) and tumor necrosis factor receptor 1 (TNFR1) by B cell-derived ligands, tumor necrosis factor (TNF) and lymphotoxins (LT) α and β.18-23 However, prion accumulation in SLOs can also occur in the absence of mature FDCs. Though lack of TNFR1 signaling can prevent prion accumulation in the spleens of i.p.-inoculated mice, PrPSc levels and prion infectivity are readily detected in TNFR1−/− and TNFα−/− lymph nodes infected with RML prions.24,25 In addition, unlike mice lacking LT signaling components, RML-infected TNFR1−/− and TNFα−/− mice succumb to terminal disease at a relatively high rate upon i.p. prion inoculation, indicating that prions are still effectively transmitted to the CNS in the absence of TNFR1 signaling. Since mature FDCs are undetectable in TNFR1−/− lymph nodes, these findings present an apparent paradox, as earlier studies had clearly demonstrated a crucial role for FDCs in SLO prion colonization. Moreover, it implies that LTβR signaling is required for prions to accumulate in lymph nodes, whereas TNFR1 signaling is dispensable. This is in contrast to the spleen, which appears to require both LTβR and TNFR1 signaling. The reason for these curious differences between spleen and lymph node with respect to their ability to accumulate prions was unknown until recently.

Requirement for LTβR Signaling in Peripheral Prion Accumulation

Recently, in an effort to determine whether continuous LTβR signaling was required for prions to colonize TNFR1−/− lymph nodes, we investigated the ability of prions to colonize SLOs of RML-infected TNFR1−/− mice treated repeatedly with an LTβR-Ig decoy antibody, which effectively blocks LTβR-dependent signaling for the duration of the experiment.26 Using this experimental paradigm, we discovered that that lymph nodal prion accumulation in the absence of TNFR1 signaling is still LTβR signaling-dependent27 (Fig. 1). This finding raises interesting issues regarding the mechanisms controlling prion accumulation in lymph nodes. First of all, the fact that transient loss of LTβR signaling was sufficient to block TNFR1-independent prion accumulation in lymph nodes indicates that prion accumulation in lymph nodes specifically requires LTβR signaling and is not simply prevented by general developmental defects or architectural disruptions caused by lack of LT signaling in genetic models of LT or LTβR deficiency. Second, our results implied that LTβR signaling was playing at least two distinct roles in prion accumulation in SLOs: (1) in the maintenance of FDCs and (2) in the maintenance of some other unidentified cell type or lymph node structure critically involved in lymph nodal prion accumulation. Therefore, our next task was to identify this LTβR-dependent lymph nodal structure.

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Figure 1. PrPSc accumulation in TNFR1−/− lymph nodes requires LTβR signaling independent.27 C57BL/6 (WT) or TNFR1−/− mice inoculated i.p. with 6 log LD50 RML6 and treated weekly with control Ig or LTβR-Ig were sacrificed at 60 d.p.i. Prion infectivity titers in mesenteric lymph node (mLN) homogenates from individual mice were then measured using the scrapie cell assay. Whereas WT-Ig and TNFR1−/−-Ig mLNs all harbored ≥ 6.1 log TCI units/g tissue, prion infectivity in WT-LTβR-Ig and TNFR1−/−-LTβR-Ig mLNs was reduced by at least 2.5 log TCI units/g tissue.

High Endothelial Venules as Novel sites of Prion Entry into SLOs

In order to identify LTβR-dependent cells other than FDCs in lymph nodes, we performed an immunohistochemical screen of spleens and mesenteric lymph nodes from wild-type mice, TNFR1−/− mice and TNFR1−/− mice treated with the LTβR-Ig decoy antibody for cell markers whose expression correlated with ability to accumulate prions. Using this screen, we identified one stromal cell marker—mucosal addressin cell adhesion molecule 1 (MadCam1)—which recognized a structure that persisted in TNFR1−/− lymph nodes but was conspicuously absent from TNFR1−/− lymph nodes after LTβR-Ig treatment. These structures were identified as high endothelial venules (HEVs)—the primary point of entry for lymphocytes into lymph nodes. Consistent with the ability of prions to colonize spleens and lymph nodes of TNF- and/or LT-deficient mice, HEVs are found in lymph nodes but not spleens,28 and HEV maintenance is dependent on LTβR signaling but not TNFR1.29 Moreover, we identified sites of PrPSc-HEV overlap in TNFR1−/−-Ig mLNs using both a histoblotting co-staining technique27 and a highly sensitive fluorescent amyloid-binding dye known as a luminescent conjugated polymer30-33 (i.e., p-FTAA; Fig. 2). This indicated that HEVs might replicate prions and/or serve as points of entry for prions or prion-harboring lymphocytes (Fig. 3). The identification of HEVs as potential sites of FDC-independent SLO prion colonization provides plausible explanations for a number of previous observations about prion colonization of SLOs. For example, FDC-deficient mice can succumb to scrapie even in the absence of detectable splenic prion titers.34 It is also known that prions can accumulate at sites of chronic inflammation. In most cases this could be attributed to ectopic development of FDC networks35-37 which are now known to arise from ubiquitous perivascular precursors.38 However, we also previously observed FDC-independent, LTβR-dependent prion accumulation in granulomas,39 which might be the result of ectopic HEV formation. Finally, we previously reported that macrophages were sites of prion accumulation in FDC-deficient TNFR1−/− lymph nodes. Since LTβR signaling did not alter most macrophage populations in lymph nodes, this was difficult to explain mechanistically. However, the identification of HEVs as probable entry sites for prions into lymph nodes suggests that de-differentiated HEVs may act as a physical barrier between prions in the bloodstream and macrophages within the lymph nodes (Fig. 3).

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Figure 2. PrPSc is present both in and around MadCam1-positive HEVs in TNFR1−/−-Ig mesenteric lymph nodes.27TNFR1−/− mice inoculated i.p. with 6 log LD50 RML6 and treated weekly with control Ig were sacrificed at 60 d.p.i. Immunofluorescence (A–I) and histoblots (J and K) were then performed on frozen sections from prion-infected TNFR1−/−-Ig mesenteric lymph nodes. Co-IF with anti-serum (XN) against PrP (green; (A) and MadCam1 (red; (B) showed points of intense PrP immunoreactivity localized to HEVs (C). Confocal co-IF with the amyloid-binding dye, p-FTAA (green); (D) and MadCam1 (red); (E) and (F) revealed some points of PrPSc association with HEVs (F); however much of the PrPSc was present outside of HEVs (I). Histoblots pre-stained with PNAd antibody and developed with AP (pink); (J) also revealed some prion-infected HEVs (black arrows), some non-infected HEVs (white arrow) and some PrPSc deposits that were not HEV-associated (yellow arrow). (K) Total numbers of PNAd-positive HEVs in histoblot co-stains were counted and scored as PrPSc-positive (PrPSc+; black) or PrPSc-negative (PrPSc+; white) and total PrPSc deposits were counted and scored as PNAd-positive (PNAd+; black) or PNAd-negative (PNAd; white). 35% of HEVs were PrPSc-positive and 58% of PrPSc deposits were PNAd-positive. Size bars in A–f = 50 μm. Size bars in G–I = 100 μm.

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Figure 3. Possible mechanisms of TNFR1- and LTβR-controlled prion entry into lymph nodes. (A) Under normal conditions prions in the bloodstream are delivered to lymph nodes within hematopoietic cells (scenarios I and II) or as naked prions (scenario III). Prion-containing hematopoietic cells are taken up in HEVs by virtue of the classical PNAd:L-selectin interaction between lymphocytes and HEV endothelial cells (scenario I). Alternatively, prions may utilize a direct interaction between PrPC expressed on HEV endothelial cells and PrPSc, either free-floating (scenario III) or tethered to a hematopoietic cell membrane (scenario II). Once inside lymph nodes, prions are transported to the B cell follicles, where they are taken up by FDCs, replicated and finally transferred to peripheral nerves. (B) In the absence of TNFR1 signaling, the uptake of prions into lymph nodes is unaffected, but mature FDCs are de-differentiated. In the absence of mature FDCs, prions are engulfed by macrophages where they are degraded. However, at high enough titers, the number of prion molecules overwhelms the capacity of macrophages to efficiently degrade them, and prions accumulate and are transferred to peripheral nerves regardless of the fact that FDCs are absent. (C) In the absence of LTβR signaling, both FDCs and HEVs are de-differentiated. De-differentiated HEVs downregulate the expression of cell surface adhesion molecules (e.g., PNAd or PrPC), which are required for the uptake of lymphocytes and/or prions into lymph nodes. Hence, the absence of FDCs in lymph nodes is inconsequential in this case, as prions can no longer enter lymph nodes or access the B cell follicles.

B Cell-Independent Prion Accumulation

FDC maintenance requires B cell-derived TNFα and LTα/β19,20 Accordingly, ablation of B cells, and hence loss of LTα/β and TNFα ligands, prevents prion deposition in SLOs.34,40 However, LTα/β signaling to HEVs appears not to depend on B cells, as HEVs do not de-differentiate when B cells are absent.29 This indicates that the LTα/β ligands are derived from a different cell in the case of HEV LTβR signaling. However, the identity of the LTα/β-producing cell responsible for LTβR signaling to HEVs was unknown until recently. A recent study indicates that dendritic cells (DCs) are the likely providers of LTα/β signal to HEVs,41 confirming that LTβR signaling in HEVs is B cell-independent. In the context of SLO prion colonization, this finding provides an explanation as to why prion neuroinvasion has been observed in the absence of B cells in certain instances, as LTβR signaling to HEVs would be expected to be unaffected in this scenario.34,42 However, the fact remains that the incidence of neuroinvasion is significantly diminished in most mice lacking functional B cells, which is inconsistent with the TNFR1−/− phenotype and with the theory that lymph nodal prion replication is B cell-independent. What could be the reason for this? One possibility is that B cells not only provide LTα/β ligands to FDCs, but are also required for efficient transport of prions to the lymph node. Though levels of prion infectivity is relatively low in B cells,43,44 and previous studies have excluded B cells as major sites of prion replication,40 it is still possible that B cells serve as transient, yet important delivery conduits to HEVs (Fig. 3). This would explain the apparent paradox between HEVs being unaffected by a lack of B cells and yet B cells still being required for prions to accumulate in lymph nodes. This conjecture is further supported by a recent study showing that B cells are required for disseminating prions between draining and non-draining SLO.45

Cells Required for Delivery, Uptake and Replication of Prions in Lymph Nodes

The ability of TNFR1−/− lymph nodes to harbor prion infectivity has been interpreted as evidence for the possible existence of alternative, non-FDC prion-replicating cells in SLOs. Since points of co-localization were found between PrPSc and HEVs,27 it is possible that HEVs are alternative sites of non-FDC prion replication in lymph nodes. However, given the known physiology of HEVs, it seems more likely that HEVs serve as regulated entry portals for prions into lymph nodes, rather than as sites of prion replication. In any case, FDC-independent prion accumulation and/or replication is certainly not restricted to HEVs, since PrPSc was also identified outside of HEVs in TNFR1−/− lymph nodes (Fig. 2).

Other likely candidates for non-FDC, prion-replicating cells include macrophages. It is known that PrPSc is localized to macrophages in prion-infected TNFR1−/− mLNs25 and in spleens with PrPC-deficient FDCs.46 However, prion replication was not observed in splenic macrophage populations,46 and more recently, it has been shown that FDC-restricted PrPC expression is necessary and sufficient to support splenic prion replication.7,47 This indicates that there are no non-FDC prion-replicating cells in SLOs, and instances of FDC-independent neuroinvasion are the result of prion accumulation in SLOs in the vicinity of peripheral nerves. However, it is possible that lymph nodes and other SLOs are fundamentally different from the spleen with respect to which cell populations are capable of replicating prions. Indeed, the involvement of HEVs (which do not exist in the spleen) in lymph nodal prion entry and the requirement for TNFR1 signaling in the spleen but not lymph nodes in prion accumulation indicates that there are key differences between these two lymphoid organs with respect to their ability to acquire and accumulate prions.

The other possibility is that replication per se is not required for prions to accumulate in lymph nodes or neuroinvasion. At low levels, macrophages may be capable of scavenging and degrading any prions that enter lymph nodes. However, at high enough titers, prions may overwhelm the degradative capacity of macrophages,48,49 leading to accumulation of prions in lymph nodes and finally to neuroinvasion in the absence of FDCs (Fig. 3B). Indeed, experimental evidence supports the idea that accumulation of prions in SLOs is sufficient for neuroinvasion and bona fide replication is not required.50-52 Conversely, the absence of complement factors, which facilitate antigen-mediated phagocytosis, significantly impairs the ability of prions to accumulate in SLOs without altering PrPC levels or abolishing FDCs,53,54 indicating that the ability of SLOs to take up prions is also critical for prion accumulation and neuroinvasion. However, not all instances of SLO prion colonization in the absence of FDCs can easily be explained by prion accumulation alone. For example, in a previous study we found that PrPC expression in either the stromal or the hematopoietic compartment was sufficient for lymph nodes to accumulate prion infectivity,25 which implies that prion replication can occur in both compartments in lymph nodes. However, an intriguing alternative explanation is that prion-harboring lymphocytes dock onto HEVs via the cell surface interaction between PrPSc on the infected hematopoietic cell and PrPC on the docking cell (Fig. 3A and B). This proposed mechanism seems plausible, as PrPC is expressed at relatively high levels within HEVs.27 Moreover, this theory could also explain why ME7 does not colonize TNFR1−/− lymph nodes like RML,55,56 since the ability of PrPC and PrPSc to interact might depend on specific PrPSc conformations and/or biochemical properties, which differ across prion strains. As discussed above, the hematopoietic delivery cells could be B cells. Alternatively, they may be macrophages. Once prions or prion-harboring cells have successfully invaded mLNs through HEVs, they may be transported via conduits to FDCs57 under normal conditions, where they are replicated and subsequently invade the nervous system. However, in the absence of mature FDCs, prions may remain in or be transferred to macrophages. At lower titers, macrophages may successfully degrade prions. However, at high enough titers, prions may accumulate in lymph nodes and infect peripheral nerves even in the absence of FDCs (Fig. 3B). In the absence of LTβR signaling, not only do FDCs de-differentiate but also HEVs, which may effectively prevent the uptake of prions into lymph nodes (Fig. 3C).

Remaining Questions

Although the identification of HEVs as sites of prion uptake in lymph nodes helps to explain a number of aspects of prion pathogenesis, a number of questions have yet to be clarified. For example, what is the mechanism by which prions are taken up by HEVs? Are naked prions recognized and taken up by HEVs, or must they be cell-borne? The dependence of prion colonization of lymph nodes on LTβR signaling suggests that prion uptake by HEVs may be mediated by a specific cell surface receptor whose expression depends on LTβR. However, the identity of this cell surface receptor(s) is unknown. The majority of lymphocyte entry into HEVs is initiated by the interaction between L-selectin and peripheral node addressin (PNAd;28). Whether prions require this same receptor interaction for uptake into lymph nodes is a question that might be answered with the use of blocking antibodies which disrupt this interaction.58 Alternatively, as discussed above, HEV-mediated uptake of prions might depend on a direct PrPSc-PrPC interaction. Is the HEV-dependent uptake mechanism described here also used in other SLOs besides the spleen, or is it specific to mesenteric lymph nodes? Peyer’s patches, for example, also have HEVs. However, there are molecular differences in the composition of HEVs in Peyer’s patches vs. peripheral lymph nodes.28 Hence, their role in prion uptake from the bloodstream may also differ. Finally, is HEV-mediated uptake of prions the primary mechanism of prion entry into lymph nodes, or are there alternate routes? The dramatic reduction in prion titers in TNFR1−/− lymph nodes of mice treated with LTβR-Ig suggests that entry through HEVs is the primary mechanism; however, it would nevertheless be of interest to know whether lymph nodal prion accumulation would be affected when HEV-mediated entry is blocked, yet FDCs are still functional.

Acknowledgments

T.O. is supported by a fellowship from the University of Zurich. A.A. is the recipient of a European Research Council Advanced Investigator Award, a Clinical Research Focus Program of the University of Zurich, and grants from Foundation Alliance Biosecure, the Novartis Research Foundation and the Swiss National Science Foundation.

Glossary

Abbreviations:

CNS

central nervous system

SLO

secondary lymphoid organ

PNS

peripheral nervous system

FDC

Follicular dendritic cell

LTβR

lymphotoxin β receptor

TNFR1

tumor necrosis factor receptor 1

TNFα

tumor necrosis factor α

LT

lymphotoxin

HEV

high endothelial venule

PrPC

prion protein (cellular conformation)

PrPSc

prion protein (scrapie conformation), Ig, immunoglobulin

mLN

mesenteric lymph node

MadCam1

mucosal addressin cell adhesion molecule 1

PNAd

peripheral node addressin

O’Connor T, Frei N, Sponarova J, Schwarz P, Heikenwalder M, Aguzzi A. Lymphotoxin, but not TNF, is required for prion invasion of lymph nodes. PLoS Pathog. 2012;8:e1002867. doi: 10.1371/journal.ppat.1002867.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Footnotes

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