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The Journal of Immunology, 2005, 174: 1159-1163.
Copyright © 2005 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: TLR Ligands Are Not Sufficient to Break Cross-Tolerance to Self-Antigens1

Emma E. Hamilton-Williams*, Andreas Lang{dagger}, Dirk Benke*, Gayle M. Davey{ddagger}, Karl-Heinz Wiesmüller§ and Christian Kurts2,*

* Institute of Molecular Medicine and Experimental Immunology, Friedrich-Wilhelms-Universität, Bonn, Germany; {dagger} Department of Nephrology and Clinical Immunology, University Hospital of the Rheinisch-Westfaelische Technische Hochschule, Aachen, Germany; {ddagger} Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; and § Institute for Organic Chemistry, Eberhard Karls University, Tübingen, Germany


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Cross-presentation of peripheral self-Ags by dendritic cells (DC) can induce deletion of autoreactive CTL by a mechanism termed cross-tolerance. Activation of DC by microbial TLR ligands is thought to result in adaptive immunity. However, activation of tolerogenic DC may cause autoimmunity by stimulating instead of deleting autoreactive CTL. To investigate this scenario, we have monitored the response of autoreactive CTL in specific for the transgenic self Ag, OVA, expressed in pancreatic islets of RIP-mOVA mice injected with ligands of TLR2, 3, 4, and 9. This somewhat enhanced proliferation and cytokine production, and moderately reduced the CTL number able to induce autoimmunity. Nevertheless, physiological CTL numbers were deleted before disease ensued, unless specific CD4 T cell help was provided. In conclusion, DC activation by TLR ligands was insufficient to break peripheral cross-tolerance in the absence of specific CD4 T cell help, and triggered autoimmunity by stimulating the early effector phase of autoreactive CTL only when their precursor frequency was extremely high.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Activation of dendritic cells (DC)3 is thought to be crucial for immunogenic T cell responses (1, 2, 3). Such activation can be facilitated by microbial molecular patterns binding to pattern-recognition receptors, most notably the TLR (2, 4). Their ligands include LPS (TLR4), lipopeptides such as Pam3Cys (TLR2/1), hypomethylated DNA such as CpG motives (TLR9) and dsRNA such as poly(I:C) (TLR3). TLR ligands increased proliferation, cytokine production, and cytoxicity of CTL responding to foreign Ags, when present during their priming (2, 3, 5, 6). TLR ligands can affect classical cross-priming of CTL, as mice deficient for MyD88 showed diminished CTL responses (7). Furthermore, LPS recruited additional DC classes for cross-priming (8). Because many infectious pathogens express TLR ligands, their stimulating effect on cross-priming DC appears to support anti-infectious immunity (2, 3).

Immature DC constitutively presenting tissue self-Ags can induce peripheral CD8 T cell deletion by cross-tolerance (9, 10). The transgenic RIP-mOVA model allowed the dissection of the underlying mechanisms. OVA-specific class I-restricted CD8+ T (OT-I) cells injected into RIP-mOVA mice, which expressed the model Ag OVA in pancreatic islet {beta} cells and in kidney-proximal tubules, were deleted (9). This was preceded by DC-mediated activation and proliferation of OT-I cells in the draining lymph nodes (LN), which led to diabetes after transfer of high numbers of OT-I cells. Lower numbers (0.5 x 106 or less) of OT-I cells were deleted before they could induce disease. Deletion occurred in the absence of CD4 T cell help, because RIP-mOVA mice were centrally tolerant to OVA. Providing OVA-specific help by injection of transgenic OVA-specific class II-restricted CD4+ T (OT-II) cells lowered the number of OT-I cells required for diabetes and impaired the deletion of OT-I cells (9). CD4 help is considered to be a major checkpoint controlling CD8 T cells, and TLR ligands were shown to replace some aspects of help in CTL responses to infectious pathogens (11).

Autoimmunity has been proposed to result from Ag mimicry or bystander T cell activation. An alternative mechanism, innate autoimmunity, has been suggested whereby tolerogenic DC presenting self-Ags are converted into autoimmunogenic DC by nonspecific stimuli, such as TLR ligands (12, 13, 14). The stimulating effect of these ligands on immune responses against foreign Ags and on the survival of T cells seems to support this hypothesis (2, 3, 15). However, if TLR ligands alone were sufficient to convert tolerance to immunity, then innate autoimmunity should regularly follow from infections with TLR-bearing pathogens or from the use of some vaccine adjuvants. Despite this, autoimmunity is rare, and even prevented by infections in some models (16). Furthermore, TLR ligands do not necessarily indicate the presence of pathogens, as commensal bacteria also bear these ligands. Nevertheless, there is overwhelming evidence that TLR ligands stimulate CTL immunity, at least in response to foreign Ags (2, 3, 17). Their influence on CTL tolerance to self-Ags, and their ability to trigger CTL-mediated innate autoimmunity have not yet been investigated in vivo. Here we have used the RIP-mOVA system to address this question.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice

RIP-mOVA, RIP-OVAHI, OT-I Rag–/–, OT-I wild-type, and OT-II mice were bred and maintained in the animal facilities of the Walter and Eliza Hall Institute for Medical Research (Melbourne, Australia) and of Institut für Versuchstierkunde, University Hospital of the Rheinisch-Westfaelische Technische Hochschule (Aachen, Germany) under specific pathogen-free conditions. Mice between 8 and 16 wk of age were used in accordance with local animal experimentation guidelines.

TLR ligands

LPS from Escherichia coli serotype 0127-B8, and poly(I:C) were from Sigma-Aldrich. The synthetic lipopeptides N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-[R]-cysteinyl-[S]-seryl-[S]-(lysyl)3-[S]-lysine (Pam3Cys) and N-palmitoyl-S-(1,2-bishexadecyloxy-carbonyl)ethyl-[R]-cysteinyl-[S]-(lysyl)3-[S]-(PHC)were synthesized by EMC microcollections (<www.microcollections.de>) (Tübingen, Germany). Phosphorothioate-stabilized CpG (5'-TCC ATG ACG TTC CTG ATG CT) and control GpC (5'-TCC ATG AGC TTC CTG ATG CT) oligonucleotides were synthesized by TIB Molbiol (Berlin, Germany). CpG effects were investigated in experiments separate from those using Pam3Cys and poly(I:C).

Cell transfer experiments

OT-I and OT-II cells were prepared from the spleen and LN of transgenic mice and CFSE labeled as described (9, 18). TLR ligands were injected i.p. in 300 µl of PBS 6 h before i.v. injection of OT-I cells. An emulsion of 200 µg of OVA (grade V; Sigma-Aldrich) and 100 µl of CFA was injected s.c. into the flank to prime OT-I cells. Urine glucose was monitored with urine test strips (Roche Diagnostic Systems), and diabetes was confirmed by histological analysis.

Intracellular staining and FACS analysis

LN cell suspensions were stimulated for 5 h in the presence of 1 µl/ml Golgi-Plug (BD Pharmingen), with or without 4 µM SIINFEKL peptide. After surface staining, cells were fixed and permeabilized with BD-Perm/wash (BD Pharmingen) before intracellular cytokine staining. All Abs were from BD Pharmingen. Cells staining and flow-cytometry on a FACScan (BD Immunocytometry Systems) were performed using standard protocols (9). SIINFEKL/H-2Kb-APC conjugated tetramers were incubated with blood lymphocytes for 15 min at room temperature followed by V{beta}5-FITC and CD8-PE for 15 min on ice. Dead cells were excluded by propidium iodide staining.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
TLR ligands lower the precursor frequency of autoreactive CD8 T cells able to cause diabetes

To test the effect of DC activation by TLR ligands on peripheral T cell cross-tolerance, the RIP-mOVA system was used. A protocol was chosen that mimicked a potent temporary infection, by injecting a single large dose of TLR ligands that did not cause shock symptoms. Expression of MHC II, CD80, CD86, and CD40 on all LN and splenic CD11c+ DC was strongly elevated 18 h after injection of the ligands Pam3Cys, poly(I:C), LPS, or CpG into C57BL/6 mice, when compared with mice injected with PBS, the control lipopeptide PHC, or control GpC oligonucleotide (data not shown). Thus, most DC were activated under these conditions and should be immunogenic. We tested whether this would lower the threshold number of OT-I cells required for diabetes induction in RIP-mOVA mice. Normally, 0.5 x 106 naive OT-I cells caused diabetes only occasionally (9). However, coinjection of TLR ligands significantly increased the incidence of diabetes (Table I), which reached 82% for LPS, 75% for CpG, 67% for poly(I:C) and 50% for Pam3Cys. Mice injected with the controls PBS, PHC, or GpC only sporadically developed diabetes (13%, 0%, 0%; Table I). No TLR ligand tested induced diabetes in nontransgenic mice (data not shown). Titration of TLR ligands excluded that the concentrations used were toxic (Table I). It is difficult, if not impossible, to accurately compare the diabetogenicity of TLR ligands in vivo, as their half-lives and binding characteristics to TLR will certainly vary. The present study did not aim at quantitatively comparing TLR ligands, but evaluated their effects on peripheral T cell tolerance in vivo. Our findings demonstrated that TLR ligands present in the priming phase allowed a lower number of OT-I cells to trigger diabetes,underscoring their immuno-stimulatory abilities.


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  		Table I. Incidence of diabetes in RIP-mOVA mice after coinjection of TLR ligands and naive OT-I cells

 
Lowering the number of transferred OT-I cells to 0.25 x 106 decreased the incidence of diabetes, and 0.05 x 106 OT-I cells did not cause disease with any TLR ligand coinjected (Table I). However, this T cell number was still higher than typical precursor frequencies in a normal T cell repertoire. Thus, the stimulating effect of TLR ligands was limited and may be relevant only in individuals with high precursor frequencies of autoreactive T cells, such as persons predisposed to, or suffering from autoimmune diseases.

TLR ligands stimulate the early effector phase of autoreactive CD8 T cells

To identify the underlying mechanisms, we investigated the effects of TLR ligands on the proliferation of OT-I cells, as their number is correlated with diabetes incidence in the RIP-mOVA model (9). After 3 days, more divided OT-I cells were seen in the draining LN of mice injected with poly(I:C) and in most animals that had received Pam3Cys, whereas only a marginal increase in proliferation was seen in CpG-injected mice (Fig. 1A). TLR ligands did not cause OT-I cell proliferation in nontransgenic mice (Fig. 1A). In nondraining LNs of mice injected with TLR ligands, recirculating OT-I cells were detectable by day 3 (data not shown). Recirculation was also evident at the beginning of the effector phase on day 6, as the proportions of OT-I cells in the CD8+ cells of TLR ligand-injected mice that later developed diabetes were 2- to 4-fold higher as compared with nondiabetic mice (data not shown).



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  		FIGURE 1. Effect of TLR ligands on proliferation and cytokine production of OT-I cells responding to self-Ag. A, RIP-mOVA mice and nontransgenic controls were injected with 100 µg of poly(I:C), 150 µg of Pam3Cys, 150 µg of PHC, 10 nmol of CpG, 10 nmol of GpC or PBS, followed by 1 x 106 CFSE-labeled OT-I cells 0.5 days later. Proliferation profiles of OT-I cells were assessed in the pancreatic LN at day 3. The numbers indicate the proportion of OT-I cells that have divided at least once. B, IFN-{gamma} and IL-2 production by OT-I cells in pancreatic LN V{beta}5+ CD8+ cells were determined at day 3. As a positive control, OVA/CFA was injected s.c., and the draining LN was analyzed. Ab specificity for cytokines was demonstrated by analyzing samples restimulated without Ag (example shown for CpG). These results are representative of three (CpG) or four (poly(I:C)/Pam3Cys) experiments.

 
To determine whether TLR ligands enhanced the functional capabilities of OT-I cells, we measured their production of IL-2 and IFN-{gamma}. Dividing OT-I cells activated in the presence of poly(I:C) and CpG showed a striking increase in IFN-{gamma}-production. IL-2 was moderately increased in poly(I:C)-injected and more marked in CpG-injected mice, in particular in later cell cycles. If DC activated by TLR ligands educated OT-I cells to produce more sustenance factors such as IL-2, a smaller population of OT-I cells might be able to support itself until all pancreatic islets would be destroyed (13, 19). However, no TLR ligand facilitated IL-2-production comparable to that from OT-I cells responding to OVA/CFA (Fig. 1B). Pam3Cys-injected mice showed only a minor increase in cytokine production (Fig. 1B), compatible with the reported bias of Pam3Cys and other TLR2 ligands to induce Th2 type responses and associated cytokines (20). In summary, the early effector phase of OT-I cells was moderately amplified by TLR ligands, which may have allowed lower numbers of OT-I cells to cause diabetes (Table I).

TLR ligands do not break cross-tolerance in the absence of specific CD4 T cell help

Next, we examined the effect of TLR ligands on the life span of OT-I cells. As RIP-mOVA mice develop diabetes after injection of a number of OT-I cells large enough to be tracked (9), we used RIP-OVAHI transgenic mice expressing OVA exclusively in the pancreas (21). OT-I cells adoptively transferred into these mice are activated and proliferate only in the pancreatic LNs. The expansion preceding deletion by cross-tolerance is not as marked as in RIP-mOVA mice. Diabetes does not ensue in RIP-OVAHI mice, so that deletion studies are not hampered by disease (21). These mice were coinjected with 3 x 106 naive OT-I cells and either poly(I:C), Pam3Cys, PHC, CpG DNA, or control GpC. OT-I cells in the blood were monitored by SIINFEKL/H-2Kb tetramer staining. On day 10, adoptively transferred OT-I cells were detected in all animals, whereas on day 31, these cells remained only in nontransgenic mice, but not in transgenic recipients (Fig. 2, A and B), indicating Ag-specific deletion. Importantly, OT-I cells had also disappeared from the blood of transgenic mice injected with the TLR ligands tested (Fig. 2, A and B). As the proportion of OT-I cells in the blood may not reflect their absence from other compartments, mice were rechallenged on day 31 with OVA/CFA. On day 38, neither OT-I cells, nor Ag specific IFN-{gamma}–producing CD8+ cells were detectable in any TLR ligand-injected transgenic recipient (Fig. 2, C and D), demonstrating that these cells had indeed been deleted. Re-expansion was seen in nontransgenic recipients (Fig. 2, C and D), in which remaining OT-I cells had been detected in the blood (Fig. 2, A and B). Thus, TLR ligand-activated DC did not program OT-I cells for a longer lifespan, nor induced a memory cell population. This interpretation can explain the moderate effect of TLR ligands on diabetes induction. The insufficiency of TLR ligands to break cross-tolerance may ensure that the temporary presence of pathogens, for example after trivial infections, does not result in long-term survival of autoreactive CD8 T cells.



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  		FIGURE 2. TLR ligands do not break cross-tolerance. RIP-OVAHI or nontransgenic littermates were injected with 3 x 106 OT-I cells and 100 µg of poly(I:C), 150 µg of Pam3Cys, or 150 µg of PHC (A and B), or with 10 nmol of CpG or 10 nmol of GpC (C and D). A and B, Their blood was analyzed on day 10 ({square}) and day 31 ({cjs2108}) for the proportion of SIINFEKL-Kb tetramer+ cells in the CD8+ cells. C and D, On day 31, mice were rechallenged s.c. with 200 µg of OVA/CFA, and on day 38, the total number of OT-I cells in LN and spleen ({square}) and the proportion of IFN-{gamma}-producing cells in the CD8+ cells ({cjs2108}) was determined. These results are representative of two individual experiments.

 
To rule out that TLR ligands caused systemic changes that compromised OT-I cells, for example sepsis-like immune paralysis (22), we examined their effect in the presence of a factor known to prevent cross-tolerance. This was achieved by coinjection of OVA-specific CD4 T cells (OT-II cells), which have been shown to lower the number of OT-I cells required for diabetes induction by impairing their deletion (9, 18). Coinjection of 0.05 x 106 OT-I cells with 2 x 106 OT-II cells plus poly(I:C) caused diabetes in 100% of recipient mice, in contrast to no disease in mice injected with only two of these factors (Table II). Thus, OT-II cells in the presence of TLR ligands could break cross-tolerization of OT-I cells, which excluded TLR-mediated systemic changes that may have incapacitated OT-I cells. Furthermore, this experiment demonstrated that specific CD4 T cell tolerance was required for maintaining cross-tolerance when the DC were activated by TLR ligands. Interestingly, the combination of poly(I:C) and OT-II cells allowed as few as 5 x 104 OT-I cells to cause diabetes (Table II). This observation suggested that both TLR ligands and specific helper cells are required to optimally stimulate autoreactive CD8 T cells, for example by affecting distinct phases of their response (e.g., the primary response by TLR ligands and CTL survival by specific help). In addition, TLR ligands may have improved the response of OT-II cells. The exact mechanisms underlying the cooperation between CTL, TLR ligands and CD4 T cell help clearly deserve further exploration.


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  		Table II. Provision of specific CD4 T cell help overcomes cross-tolerance in the presence of TLR

 
In summary, our study demonstrates that TLR ligands present during T cell priming enhanced the early effector phase of autoreactive CD8 T cells, reminiscent of their stimulatory effects on the early phase of CTL responses to foreign Ags (2, 3, 5, 6). Such stimulation resulted in immune pathology, but only when the precursor frequency of autoreactive CD8 T cells was unphysiologically high (Table I). Physiological CTL numbers induced autoimmunity only in the presence of a TLR ligand and of specific CD4 T cell help. Without such help, autoreactive CTL were deleted in a situation where self-Ag persisted. In the transgenic influenza virus hemagglutinin system, such persistence has been shown to be important for maintaining CD8 T cell tolerance, as CD8 T cells primed without activating signals survived after transfer into nontransgenic hosts (23). In peptide vaccination experiments, persistence of Ag presentation resulted in CD8 T cell tolerance regardless of the presence of poly(I:C) during priming (24). These studies are compatible with our interpretation that nonspecific DC-activation during priming is not sufficient to prolong the lifespan of autoreactive CD8 T cells. This supports the view that self-tolerance is a robust state with multiple checkpoints that must be overcome before autoimmunity is unleashed (19, 25, 26). In this model, the mere presence of TLR ligands, for example derived from antigenically unrelated pathogens or from commensal bacteria, would not compromise peripheral tolerance induction. Our findings do not rule out that pathogen-associated molecular patterns other than TLR ligands may be able to do so. However, they suggest that the use of TLR ligands as adjuvants to stimulate CTL responses to foreign Ags will not trigger CD8 T cell-mediated "innate autoimmunity" (14).


   Acknowledgments
 
We thank William R. Heath, Percy A. Knolle, and Andreas Limmer for critically reading the manuscript, Ton Schumacher for SIINFEKL/H-2Kb tetramers, Monika Wirtz for technical assistance, Steffi Schweisstal and Alexandra Korzen for animal husbandry and the Flow Cytometry Core Facility at the Institute of Molecular Medicine and Experimental Immunology (Bonn, Germany) for excellent assistance.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 C.K. was supported by a Heisenberg fellowship from the Deutsche Forschungsgemeinschaft (Grant Ku1063/2-1) and by a junior research group grant of the German state of Nordrhein-Westfalen. Back

2 Address correspondence and reprint requests to Dr. Christian Kurts, Institute of Molecular Medicine and Experimental Immunology, Friedrich-Wilhelms-Universität, 53105, Bonn, Germany. E-mail address: ckurts{at}web.de Back

3 Abbreviations used in this paper: RIP, rat insulin promoter; mOVA, membrane-bound form of OVA; OT-I, OVA-specific class I-restricted CD8+ T cell; OT-II, OVA-specific class II-restricted CD4+ T cell; Pam3Cys, N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-[R]-cysteinyl-[S]-seryl)-[S]-(lysyl)3-[S]-lysine; PHC, N-palmitoyl-S-(1,2-bishexadecyloxy-carbonyl)ethyl-[R]-cysteinyl-[S]-seryl-[S]-(lysyl)3-[S]-lysine; DC, dendritic cell; LN, lymph node. Back

Received for publication October 20, 2004. Accepted for publication November 30, 2004.


   References
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 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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