A paradoxical role for IFN-γ in the immune properties of mesenchymal stem cells during viral challenge

Kang, Helen S.; Habib, Misha; Chan, Jennifer; Abavana, Christina; Potian, Julius A.; Ponzio, Nicholas M.; Rameshwar, Pranela

doi:10.1016/j.exphem.2005.03.012

Cited by 52 publications

(43 citation statements)

References 37 publications

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“…21 A recent study demonstrated that viral infection can induce the production of IFN-␥ by bone marrow stromal cells, and this can mediate partial cytotoxic T lymphocyte (CTL) responses. 22 As depicted in Figure 7, secretion of IFN-␥ was detected in primary bone marrow stroma cultures from TC-PTP Ϫ/Ϫ mice and was associated with hyperphosphorylation of Stat1 in pre-B cells isolated from the bone marrow of these animals. IFN-␥ secretion leads to apoptosis, decreased number of pre-B cells expressing surface IL-7R, decreased proliferation in response to IL-7, which was associated with hypophosphorylation of downstream effectors Jak1 and Stat5.…”

Section: Discussionmentioning

confidence: 96%

TC-PTP–deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-γ

Bourdeau

Dubé

Heinonen

et al. 2007

Blood

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The T-cell protein tyrosine phosphatase (TC-PTP) is a negative regulator of the Jak/Stat cytokine signaling pathway. Our study shows that the absence of TC-PTP leads to an early bone marrow B-cell deficiency characterized by hindered transition from the pre-B cell to immature B-cell stage. This phenotype is intrinsic to the B cells but most importantly due to bone marrow stroma abnormalities. We found that bone marrow stromal cells from TC-PTP ؊ IntroductionThe T-cell protein tyrosine phosphatase (TC-PTP) is an intracellular enzyme encoded by Ptpn2. It is ubiquitously expressed, with highest levels in hematopoietic tissues (for a review, see Bourdeau et al 1 ). TC-PTP Ϫ/Ϫ mice appear physically normal until 10 to 14 days of age, at which time they progressively develop tissue mononuclear cell infiltrates. 2 Elevated levels of IFN-␥ can be measured at 19 days of age, 3 and the animals die between 21 and 35 days of age. TC-PTP Ϫ/Ϫ mice display defective hematopoiesis and immune function, characterized by anemia and splenomegaly secondary to sequestration of erythrocytes and accumulation of myeloid cells. 2 TC-PTP was also shown to interact with TRAF2 downstream of the TNF proinflammatory cytokine. This interaction inactivated Src and suppressed MAPK signaling. 4 TC-PTP has been identified as a critical regulator of colony-stimulating factor 1 (CSF-1) signaling and mononuclear phagocyte development. On CSF-1 stimulation, a deficiency in TC-PTP leads to enhanced tyrosine phosphorylation of the Grb2/Gab2/Shp2 complex by the CSF-1 receptor and increased activation of Erk. 5 These results identified TC-PTP as a key modulator of inflammatory signals as well as macrophage and lymphocyte functions.TC-PTP has been shown to control cytokine signaling events by its negative action on the Janus kinase (Jak) and signal transducer and activator of transcription (Stat) pathways (reviewed by Bourdeau et al 1 ). This cascade is crucial for hematopoietic development and cellular response to growth factors. 6 Using an in vitro approach, TC-PTP substrate-trapping mutant D/A was shown to interact with Jak1 and Jak3. 7 Stat1, Stat3, and Stat5a/5b were also identified as substrates for TC-PTP. [8][9][10] It is clear that TC-PTP is a key director of several cytokine-signaling pathways, and thus may be involved in the development of multiple hematopoietic lineages.Here, we report that bone marrow stromal cells from TC-PTP Ϫ/Ϫ mice secrete abnormally high levels of IFN-␥, resulting in constitutive phosphorylation of Stat1 in pre-B cells and altered B-cell development in the bone marrow. Our findings are novel and reflect the therapeutic potential of TC-PTP as a modulator of bone marrow stroma microenvironment that could be exploited in leukemia and other immune disorders. Materials and methods MiceGeneration of TC-PTP mutant mice was described previously. 2 Experiments were performed with mice on a mixed Balb/c-129SJ background and with mice backcrossed for 8 generation on Balb/c. All procedures were approved by the McGill University Rese...

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Section: Discussionmentioning

confidence: 96%

TC-PTP–deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-γ

Bourdeau

Dubé

Heinonen

et al. 2007

Blood

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“…Another study showed that PBMCs cultured with herpes simplex virus had reduced cytolytic activity against P815 mastocytoma cell line if MSCs were added to the cultures. 26 However, they did not test the cytolytic killing of viral-infected targets, which makes it difficult to conclude that MSCs have an effect on viral-specific T-cell lysis. We used established virusspecific CTL lines and found that MSCs had no effect on cytolytic killing of cells presenting viral antigens.…”

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confidence: 99%

Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses

Karlsson

Samarasinghe²,

Ball

et al. 2008

Blood

146

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Mesenchymal stem cells (MSCs) suppress alloantigen-induced T-cell functions in vitro and infusion of third-party MSCs seems to be a promising therapy for graft-versus-host disease (GVHD).Little is known about the specificity of immunosuppression by MSCs, in particular the effect on immunity to pathogens. We have studied how MSCs affect T-cell responses specific to Epstein-Barr virus (EBV) and cytomegalovirus (CMV). We found that EBV-and CMV-induced proliferation and interferon-␥ (IFN-␥ IntroductionHuman mesenchymal stem cells (MSCs) can differentiate into a variety of tissues, including bone, cartilage, and muscle. 1 MSCs are found in low frequency in the bone marrow but can be isolated and expanded in vitro. One important feature of MSCs is their immunoregulatory functions. MSCs suppress alloantigen and mitogen-induced proliferation, 2-4 interferon-␥ (IFN-␥) production, 5 and cytolytic killing 6,7 in vitro in a manner not restricted by the major histocompatibility complex (MHC), 3 but the mechanisms of suppression by MSCs are still largely unclear. MSCs also seem to escape recognition of alloreactive cells. 3,[8][9][10] The immunomodulatory effects of MSCs in the allogeneic setting have provided a rationale for the clinical use in graft-versus-host disease (GVHD). Severe acute GVHD after allogeneic stem cell transplantation (SCT) is associated with high mortality, but infusion of third-party MSCs seems to be a promising therapy for GVHD refractory to conventional immunosuppressive treatments. 11,12 Very little is known about the specificity of immunosuppression by MSCs and, in particular, the effect on cell-mediated immunity to infectious pathogens. This is an important issue, because infections are a major cause of morbidity and mortality after allogeneic SCT, particularly in the setting of intensive immunosuppression required for the treatment of GVHD. Two major viral pathogens in this setting are cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Between 40% and 70% of stem cell transplant recipients who are CMV-seropositive or have a seropositive donor develop CMV reactivation. [13][14][15] EBV reactivation may result in posttransplantation lymphoproliferative disease (PTLD) and occurs in 11% to 26% of SCT patients in whom selective T-cell depletion has been used for prevention of GVHD. [16][17][18] Antiviral T-cell effector functions are essential for preventing viral reactivation and progression to virus-associated disease. Thus, if MSCs have regulatory effects on antiviral cell-mediated immunity, administration of MSCs to immunocompromised patients could exacerbate their susceptibility to infectious pathogens. Indeed, at least one patient treated with MSCs for GVHD developed EBV-associated PTLD, and there have been several cases of CMV reactivation after MSC infusion. 12 However, there is insufficient clinical experience to determine whether administration of MSCs affects the development of virus-associated disease. We have therefore systematically studied how MSCs affect antiviral T-cell effector func...

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“…6 Indeed, some reports have indicated that MSCs are capable of suppressing pathogen-specific T-cell proliferation and effector function directed against herpesviruses in vitro. 7,8 However, data on the direct interaction between MSCs and microbial pathogens are sparse. Here, we demonstrate for the first time that on stimulation with inflammatory cytokines IDO-positive human MSCs exhibit a cell autonomous, broad-spectrum antimicrobial effector function directed against clinically relevant bacteria, protozoal parasites and viruses.…”

Section: Introductionmentioning

confidence: 99%

Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase

et al. 2011

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Human multipotent mesenchymal stromal cells (MSCs) exhibit multilineage differentiation potential, support hematopoiesis, and inhibit proliferation and effector function of various immune cells. On the basis of these properties, MSC are currently under clinical investigation in a range of therapeutic applications including tissue repair and immune-mediated disorders such as graft-versus-host-disease refractory to pharmacological immunosuppression. Although initial clinical results appear promising, there are significant concerns that application of MSC might inadvertently suppress antimicrobial immunity with an increased risk of infection. We demonstrate here that on stimulation with inflammatory cytokines human MSC exhibit broad-spectrum antimicrobial effector function directed against a range of clinically relevant bacteria, protozoal parasites and viruses. Moreover, we identify the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) as the underlying molecular mechanism. We furthermore delineate significant differences between human and murine MSC in that murine MSC fail to express IDO and inhibit bacterial growth. Conversely, only murine but not human MSC express inducible nitric oxide synthase on cytokine stimulation thus challenging the validity of murine in vivo models for the preclinical evaluation of human MSC. Collectively, our data identify human MSC as a cellular immunosuppressant that concurrently exhibits potent antimicrobial effector function thus encouraging their further evaluation in clinical trials.

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A paradoxical role for IFN-γ in the immune properties of mesenchymal stem cells during viral challenge

Cited by 52 publications

References 37 publications

TC-PTP–deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-γ

TC-PTP–deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-γ

Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses

Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase

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