IL-34 is a Treg-specific cytokine and mediates transplant tolerance

Bézie, Séverine; Picarda, Élodie; Ossart, Jason; Tesson, Laurent; Usal, Claire; Renaudin, Karine; Anegón, Ignacio; Guillonneau, Carole

doi:10.1172/jci81227

Cited by 106 publications

(148 citation statements)

References 54 publications

(76 reference statements)

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“…Recent studies revealed that IL-34 drives the differentiation of monocytes into immunosuppressive M2 and that human macrophages cultured in the presence of IL-34 are able to expand Treg cells. Interestingly, IL-34-expanded Treg cells display a stronger suppressive activity compared to non-IL-34-expanded Treg cells [135,136]. This widens the spectrum of action of IL-34 towards immune tolerance.…”

Section: Il-34mentioning

confidence: 95%

Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets

et al. 2017

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In recent years, the landscape of pro- and anti-inflammatory cytokines has rapidly expanded with the identification of new members proven to be involved at different extent in the pathogenesis of chronic immune mediated inflammatory diseases including rheumatoid arthritis (RA). The advance of our understanding of mediators involved in the pathogenesis of RA and in consequence, the development of novel targeted therapies is necessary to provide patients not responding to currently available strategies with novel compounds. The aim of this review article is to provide an overview on recently identified cytokines, emphasizing their pathogenic role and therapeutic potential in RA. A systematic literature review was performed to retrieve articles related to every cytokine discussed in the review. In some cases, evidence from animal models and RA patients is already consistent to move forward into drug development. In others, conflicting observation and the paucity of data require further investigations.Forty years after the discovery of IL-1, the landscape of cytokines is continuously expanding with increasing possibilities to develop novel therapeutic strategies in RA. Electronic supplementary material The online version of this article (10.1186/s41927-017-0001-8) contains supplementary material, which is available to authorized users.

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Section: Il-34mentioning

confidence: 95%

Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets

et al. 2017

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“…In this issue, Bézie et al demonstrate a new connection between macrophages and Tregs that mediates the immunosuppressive properties of these cells (11). IL-34 shares several characteristics with macrophage CSF (M-CSF or CSF1), which is necessary for the differentiation of monocytes, macrophages, and some DCs.…”

Section: Il-34: a New Player In Immune Tolerancementioning

confidence: 99%

“…In a murine heart transplant model in which CD40/CD154 blockade plus donor splenocyte transfusion promotes longterm survival, myeloid-derived suppressor cells are required for tolerance and Treg induction (18,20). Do the IL-34-treated macrophages described by Bézie et al (11) and the myeloid-derived suppressor cells represent overlapping suppressor cell populations, and do myeloid-derived suppressor cells induce IL-34-expressing Tregs?…”

Section: Il-34: a New Player In Immune Tolerancementioning

confidence: 99%

Transplant tolerance: a new role for IL-34

Kim¹,

Turka²

2015

Journal of Clinical Investigation

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C o m m e n t a r y Tregs and immune toleranceTolerance to self-and foreign antigens is created by a combination of the deletion of antigen-reactive T cells and control of the remaining cells by a specialized population of T cells known as Tregs. The best-characterized lineage of Tregs is defined by expression of the X-linked transcription factor FOXP3, and this population is essential for the maintenance of self-tolerance (1). The importance of these FOXP3 + Tregs in the preservation of self-tolerance is perhaps best exemplified by the development of multiorgan autoimmunity in patients with IPEX syndrome and in scurfy mice, both of which harbor loss-of-function mutations in the FOXP3-encoding gene.Tregs also play a critical role in organ and tissue transplantation, and abundant evidence from patients and animal models implicates these cells in long-term allograft survival and tolerance. As the frequency of T cell precursors that are capable of responding to alloantigens is extremely high (~1%-10%; ref. 2), tolerance is likely established by deletion of large numbers of these alloreactive cells (3). However, deletion of alloreactive T cells is incomplete, and new alloreactive T cells are continuously generated in the thymus; therefore, maintaining tolerance to the allograft requires continual monitoring of alloreactive cells in the periphery by Tregs. Indeed, Tregs have been implicated to be essential for graft acceptance in the vast majority of experimental transplant tolerance models.Like other T cell populations, Tregs mature in the thymus as part of normal lymphoid development. These so-called "natural" or "thymic" Tregs express TCRs (T cell receptors for antigen) that are preferentially attuned to recognize self-antigen. -T cells into FOXP3 + Tregs through reduced expression of T cell costimulatory molecules and secretion of cytokines, such as IL-10 and TGF-β (7-9). Macrophages, which survey the extracellular space by engulfing antigen and activating patrolling T cells, play a role in tolerance induction and maintenance as well. Moreover, suppressive macrophages can induce Treg differentiation (10), though the mechanism has not been completely elucidated. IL-34: a new player in immune toleranceIn this issue, Bézie et al. demonstrate a new connection between macrophages and Tregs that mediates the immunosuppressive properties of these cells (11). IL-34 shares several characteristics with macrophage CSF (M-CSF or CSF1), which is necessary for the differentiation of monocytes, macrophages, and some DCs. While there is little sequence homology between IL-34 and M-CSF, both cytokines promote monocyte lineage survival through binding their shared receptor CSF1R (also known as CD115) (12). IL-34 is largely considered to promote macrophage, monocyte, and DC survival following its release from various tissues in response to inflammation. Bézie and colleagues now provide evidence that IL-34 is also expressed by rodent and human Tregs and promotes the suppressive properties of macrophages, which in turn promote the up...

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“…We have been studying in depth for several years a subset of CD8 + Tregs that is characterized by the low expression of the marker CD45RC (1,7,(13)(14)(15)(16)(17)(18)(19)(20). We have demonstrated that following CD40Ig treatment, only CD8 + CD45RC low T cells are capable of infectious allogeneic tolerance through dominant suppression by expression of IFN-g, which in turn induces IDO expression, but also expression of fibrinogen-like protein 2/fibroleukin (21) and IL-34 (20).…”

mentioning

confidence: 99%

“…We have demonstrated that following CD40Ig treatment, only CD8 + CD45RC low T cells are capable of infectious allogeneic tolerance through dominant suppression by expression of IFN-g, which in turn induces IDO expression, but also expression of fibrinogen-like protein 2/fibroleukin (21) and IL-34 (20). We also showed that CD8 + CD45RC low T cell and plasmacytoid dendritic cells (pDC) interactions were necessary for suppression of CD4 + T cells and involved different mechanisms modulated by the presence of cell contact between CD8 + Tregs, pDCs, and CD4 + effector cells (14).…”

mentioning

confidence: 99%

Compensatory Regulatory Networks between CD8 T, B, and Myeloid Cells in Organ Transplantation Tolerance

Bézie

Picarda

Ossart

et al. 2015

The Journal of Immunology

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In transplantation tolerance, numerous regulatory populations have the capacity to inhibit allograft rejection; however, their compensatory capacities have never been clearly evidenced. We have previously demonstrated that the tolerogenic effect mediated by CD8+CD45RClow regulatory T cells (Tregs) in a model of organ transplantation with CD40Ig could be abrogated by permanent depletion of CD8+ cells that resulted in allograft rejection in half of the recipients. This result demonstrated that CD8+ Tregs were essential, but also that half of the recipients still survived indefinitely. We also demonstrated that no other regulatory populations, besides CD8+ Tregs, could induce and maintain allograft tolerance in CD40Ig-treated tolerant animals. In the current study, we analyzed the mechanisms that arose following CD8+ Treg depletion and allowed establishment of networks of new regulatory cells to maintain allograft survival. We identified regulatory B cells (Bregs) and regulatory myeloid cells (RegMCs) as being responsible of the maintenance of the long-term allograft survival. We demonstrated that both regulatory cell subsets efficiently inhibited antidonor immune responses in adoptively transferred recipients. Although Bregs were induced, they were not essential for the maintenance of the graft as demonstrated in IgM-deficient recipients. In addition, we showed that RegMCs were the most suppressive and acted alone, whereas Bregs activity was associated with increased suppressive activity of other subsets in adoptively transferred recipients. Altogether, to our knowledge, we demonstrated in this study for the first time the emergence of both Bregs and RegMCs following Tregs depletion and highlighted the importance of regulatory cell networks and their synergistic potential in transplantation.

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IL-34 is a Treg-specific cytokine and mediates transplant tolerance

Cited by 106 publications

References 54 publications

Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets

Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets

Transplant tolerance: a new role for IL-34

Compensatory Regulatory Networks between CD8 T, B, and Myeloid Cells in Organ Transplantation Tolerance

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