Rapid rebound of the Treg compartment in DEREG mice limits the impact of Treg depletion on mycobacterial burden, but prevents autoimmunity.

2.50
Hdl Handle:
http://hdl.handle.net/10033/332349
Title:
Rapid rebound of the Treg compartment in DEREG mice limits the impact of Treg depletion on mycobacterial burden, but prevents autoimmunity.
Authors:
Berod, Luciana; Stüve, Philipp; Varela, Filipa; Behrends, Jochen; Swallow, Maxine; Kruse, Friederike; Krull, Freyja; Ghorbani, Peyman; Mayer, Christian T; Hölscher, Christoph; Sparwasser, Tim ( 0000-0001-5645-902X )
Abstract:
The development of an effective vaccine against tuberculosis (Tb) represents one of the major medical challenges of this century. Mycobacterium bovis Bacille Calmette-Guerin (BCG), the only vaccine available at present, is mostly effective at preventing disseminated Tb in children, but shows variable protection against pulmonary Tb, the most common form in adults. The reasons for this poor efficacy are not completely understood, but there is evidence that T regulatory cells (Tregs) might be involved. Similarly, Tregs have been associated with the immunosuppression observed in patients infected with Tb and are therefore believed to play a role in pathogen persistence. Thus, Treg depletion has been postulated as a novel strategy to potentiate M. bovis BCG vaccination on one side, while on the other, employed as a therapeutic approach during chronic Tb infection. Yet since Tregs are critically involved in controlling autoimmune inflammation, elimination of Tregs may therefore also incur the danger of an excessive inflammatory immune response. Thus, understanding the dynamics and function of Tregs during mycobacterial infection is crucial to evaluate the potential of Treg depletion as a medical option. To address this, we depleted Tregs after infection with M. bovis BCG or Mycobacterium tuberculosis (Mtb) using DEREG mice, which express the diphtheria toxin (DT) receptor under the control of the FoxP3 locus, thereby allowing the selective depletion of FoxP3+ Tregs. Our results show that after depletion, the Treg niche is rapidly refilled by a population of DT-insensitive Tregs (diTregs) and bacterial load remains unchanged. On the contrary, impaired rebound of Tregs in DEREG × FoxP3GFP mice improves pathogen burden, but is accompanied by detrimental autoimmune inflammation. Therefore, our study provides the proof-of-principle that, although a high degree of Treg depletion may contribute to the control of mycobacterial infection, it carries the risk of autoimmunity.
Citation:
Rapid rebound of the Treg compartment in DEREG mice limits the impact of Treg depletion on mycobacterial burden, but prevents autoimmunity. 2014, 9 (7):e102804 PLoS ONE
Journal:
PloS one
Issue Date:
2014
URI:
http://hdl.handle.net/10033/332349
DOI:
10.1371/journal.pone.0102804
PubMed ID:
25050936
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
publications of the TwinCore unit Infection immunology

Full metadata record

DC FieldValue Language
dc.contributor.authorBerod, Lucianaen
dc.contributor.authorStüve, Philippen
dc.contributor.authorVarela, Filipaen
dc.contributor.authorBehrends, Jochenen
dc.contributor.authorSwallow, Maxineen
dc.contributor.authorKruse, Friederikeen
dc.contributor.authorKrull, Freyjaen
dc.contributor.authorGhorbani, Peymanen
dc.contributor.authorMayer, Christian Ten
dc.contributor.authorHölscher, Christophen
dc.contributor.authorSparwasser, Timen
dc.date.accessioned2014-10-09T08:05:51Zen
dc.date.available2014-10-09T08:05:51Zen
dc.date.issued2014en
dc.identifier.citationRapid rebound of the Treg compartment in DEREG mice limits the impact of Treg depletion on mycobacterial burden, but prevents autoimmunity. 2014, 9 (7):e102804 PLoS ONEen
dc.identifier.issn1932-6203en
dc.identifier.pmid25050936en
dc.identifier.doi10.1371/journal.pone.0102804en
dc.identifier.urihttp://hdl.handle.net/10033/332349en
dc.description.abstractThe development of an effective vaccine against tuberculosis (Tb) represents one of the major medical challenges of this century. Mycobacterium bovis Bacille Calmette-Guerin (BCG), the only vaccine available at present, is mostly effective at preventing disseminated Tb in children, but shows variable protection against pulmonary Tb, the most common form in adults. The reasons for this poor efficacy are not completely understood, but there is evidence that T regulatory cells (Tregs) might be involved. Similarly, Tregs have been associated with the immunosuppression observed in patients infected with Tb and are therefore believed to play a role in pathogen persistence. Thus, Treg depletion has been postulated as a novel strategy to potentiate M. bovis BCG vaccination on one side, while on the other, employed as a therapeutic approach during chronic Tb infection. Yet since Tregs are critically involved in controlling autoimmune inflammation, elimination of Tregs may therefore also incur the danger of an excessive inflammatory immune response. Thus, understanding the dynamics and function of Tregs during mycobacterial infection is crucial to evaluate the potential of Treg depletion as a medical option. To address this, we depleted Tregs after infection with M. bovis BCG or Mycobacterium tuberculosis (Mtb) using DEREG mice, which express the diphtheria toxin (DT) receptor under the control of the FoxP3 locus, thereby allowing the selective depletion of FoxP3+ Tregs. Our results show that after depletion, the Treg niche is rapidly refilled by a population of DT-insensitive Tregs (diTregs) and bacterial load remains unchanged. On the contrary, impaired rebound of Tregs in DEREG × FoxP3GFP mice improves pathogen burden, but is accompanied by detrimental autoimmune inflammation. Therefore, our study provides the proof-of-principle that, although a high degree of Treg depletion may contribute to the control of mycobacterial infection, it carries the risk of autoimmunity.en
dc.language.isoenen
dc.rightsArchived with thanks to PloS oneen
dc.titleRapid rebound of the Treg compartment in DEREG mice limits the impact of Treg depletion on mycobacterial burden, but prevents autoimmunity.en
dc.typeArticleen
dc.identifier.journalPloS oneen

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