IFN-γ– and IL-10–expressing virus epitope-specific Foxp3+ T reg cells in the central nervous system during encephalomyelitis

Zhao, Jingxian; Fett, Craig; Trandem, Kathryn; Fleming, Erica; Perlman, Stanley

doi:10.1084/jem.20110236

Cited by 91 publications

(121 citation statements)

References 26 publications

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“…Our data also suggest that nTreg could contribute directly to the pathogenesis via the production of IFN-␥ and to a lesser extent IL-4, both of which are associated with ECM (7,44). Although never described in ECM, this observation is in line with two recent reports describing the polarization of Treg into IFN-␥-producing Th1 cells following acute infection by Mycobacterium tuberculosis (45) and Toxoplasma gondii (46) and in other inflammatory settings (47)(48)(49)(50)(51). In addition, nTreg plasticity was associated with a modulation of their transcription program (expression of T-bet and possible downregulation of Foxp3) (45-47, 51, 52).…”

Section: Discussionsupporting

confidence: 91%

Suppression of CD4⁺Effector Responses by Naturally Occurring CD4⁺CD25⁺Foxp3⁺Regulatory T Cells Contributes to Experimental Cerebral Malaria

et al. 2016

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The role of naturally occurring CD4؉ CD25 ؉ Foxp3 ؉ regulatory T cells (nTreg) in the pathogenesis of cerebral malaria (CM), which involves both pathogenic T cell responses and parasite sequestration in the brain, is still unclear. To assess the contribution and dynamics of nTreg during the neuropathogenesis, we unbalanced the ratio between nTreg and naive CD4 ؉ T cells in an attenuated model of Plasmodium berghei ANKA-induced experimental CM (ECM) by using a selective cell enrichment strategy. We found that nTreg adoptive transfer accelerated the onset and increased the severity of CM in syngeneic C57BL/6 (B6) P. berghei ANKA-infected mice without affecting the level of parasitemia. In contrast, naive CD4 ؉ T cell enrichment prevented CM and promoted parasite clearance. Furthermore, early during the infection nTreg expanded in the spleen but did not efficiently migrate to the site of neuroinflammation, suggesting that nTreg exert their pathogenic action early in the spleen by suppressing the protective naive CD4؉ T cell response to P. berghei ANKA infection in vivo in both CM-susceptible (B6) and CM-resistant (B6-CD4 ؊/؊ ) mice. However, their sole transfer was not sufficient to restore CM susceptibility in two CM-resistant congenic strains tested. Altogether, these results demonstrate that nTreg are activated and functional during P. berghei ANKA infection and that they contribute to the pathogenesis of CM. They further suggest that nTreg may represent an early target for the modulation of the immune response to malaria.

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Section: Discussionsupporting

confidence: 91%

Suppression of CD4⁺Effector Responses by Naturally Occurring CD4⁺CD25⁺Foxp3⁺Regulatory T Cells Contributes to Experimental Cerebral Malaria

et al. 2016

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“…Recently, it has been described that Foxp3 ϩ Treg cells may coexpress transcription factors typical of effector TH1, TH2, and TH17, such as Tbet, GATA3, and Stat3 (26)(27)(28). The expansion of these T regulatory subsets is driven by the TH cytokines (IFN-␥, IL-4, IL-17) and occurs in parallel with the related effectors (27,38), and, in definite pathological conditions, such as strong pathogen-induced immunopathology, it was reported that these Treg cells also produce the TH-related cytokines (39,40) without losing the regulatory ability. With these premises, it is conceivable that Treg cells acquire (or reacquire) the TH1 phenotype, with the expression of Tbet and also the production of IFN-␥, in response to the great amounts of IFN-␥ released under the influence of MDDC-PfSE.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the Immune and Inflammatory Responses by Plasmodium falciparum Schizont Extracts: Role of Myeloid Dendritic Cells in Effector and Regulatory Functions of CD4 ⁺ Lymphocytes

et al. 2013

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eThe optimal immune response to malaria infection comprises rapid induction of inflammatory responses promptly counteracted by regulatory mechanisms to prevent immunopathology. To evaluate the role of dendritic cells (DC) in the balance of parasite-induced inflammatory/anti-inflammatory mechanisms, we studied the activity of monocyte-derived dendritic cells (MDDC), previously exposed to soluble extracts of Plasmodium falciparum-infected red blood cells (PfSE), in the differentiation of CD4 cells isolated from donors never exposed to malaria infection. We show that MDDC exposed to PfSE are extremely efficient to induce a contemporary differentiation of TH1 effector cells and T regulatory (Treg) cells in CD4 T cells even when exposed to low concentrations of parasitic extracts. Treg cells induced by MDDC infected with PfSE (MDDC-PfSE) produce transforming growth factor beta (TGF-␤) and interleukin 10 (IL-10) and are endowed with strong suppressive properties. They also show phenotypical and functional peculiarities, such as the contemporary expression of markers of Treg and TH1 differentiation and higher sensitivity to TLR4 ligands both inducing an increasing production of suppressive cytokines. On the whole, our data indicate that MDDC exposed to PfSE orchestrate a well-balanced immune response with timely differentiation of TH1 and Treg cells in CD4 cells from nonimmune donors and suggest that, during the infection, the role of MDCC could be particularly relevant in low-parasitemia conditions.

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“…During MHV infection, virus-specific CD4 + T cells can acquire a Treg phenotype (42). Thus, the interpretation that Tregs can selectively contribute to immune privilege of CNS self-antigens during viral infection whereas the initiation of protective T cell responses remains unaltered raises the question of how such selectivity is achieved.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cells Selectively Preserve Immune Privilege of Self-Antigens during Viral Central Nervous System Infection

Cervantes-Barragán

Firner

Bechmann

et al. 2012

The Journal of Immunology

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Regulatory T cells (Tregs) are important for the attenuation of immune reactions. During viral CNS infections, however, an indiscriminate maintenance of CNS immune privilege through Treg-mediated negative regulation could prevent autoimmune sequelae but impair the control of viral replication. We analyzed in this study the impact of Tregs on the development of acute viral encephalomyelitis, T cell-mediated antiviral protection, and prevention of CNS autoimmunity following intranasal infection with the gliatropic mouse hepatitis virus strain A59. To assess the contribution of Tregs in vivo, we specifically depleted CD4+Foxp3+ T cells in a diphtheria toxin-dependent manner. We found that depletion of Tregs had no impact on viral distribution and clearance and did not significantly alter virus-specific CD4+ and CD8+ T cell responses. However, Treg depletion led to a more severe CNS inflammation associated with neuronal damage. Dissection of the underlying immunopathological mechanisms revealed the elaborate Treg-dependent regulation of self-reactive CD4+ T cell proliferation within the CNS-draining lymph node and downtuning of CXCR3 expression on T cells. Taken together, these results suggest that Tregs preserve CNS immune privilege through selective control of CNS-specific Th cells while keeping protective antiviral immunity fully operative.

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IFN-γ– and IL-10–expressing virus epitope-specific Foxp3+ T reg cells in the central nervous system during encephalomyelitis

Abstract: Pathogen-specific Foxp3+ T reg cells can be identified on the basis of cytokine production, are detected in naive T cell populations, and exhibit suppressive ability toward effector T cells with the same antigen specificity.

Cited by 91 publications

References 26 publications

Suppression of CD4⁺Effector Responses by Naturally Occurring CD4⁺CD25⁺Foxp3⁺Regulatory T Cells Contributes to Experimental Cerebral Malaria

Suppression of CD4⁺Effector Responses by Naturally Occurring CD4⁺CD25⁺Foxp3⁺Regulatory T Cells Contributes to Experimental Cerebral Malaria

Modulation of the Immune and Inflammatory Responses by Plasmodium falciparum Schizont Extracts: Role of Myeloid Dendritic Cells in Effector and Regulatory Functions of CD4 ⁺ Lymphocytes

Regulatory T Cells Selectively Preserve Immune Privilege of Self-Antigens during Viral Central Nervous System Infection

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IFN-γ– and IL-10–expressing virus epitope-specific Foxp3+ T reg cells in the central nervous system during encephalomyelitis

Abstract: Pathogen-specific Foxp3+ T reg cells can be identified on the basis of cytokine production, are detected in naive T cell populations, and exhibit suppressive ability toward effector T cells with the same antigen specificity.

Cited by 91 publications

References 26 publications

Suppression of CD4+Effector Responses by Naturally Occurring CD4+CD25+Foxp3+Regulatory T Cells Contributes to Experimental Cerebral Malaria

Suppression of CD4+Effector Responses by Naturally Occurring CD4+CD25+Foxp3+Regulatory T Cells Contributes to Experimental Cerebral Malaria

Modulation of the Immune and Inflammatory Responses by Plasmodium falciparum Schizont Extracts: Role of Myeloid Dendritic Cells in Effector and Regulatory Functions of CD4 + Lymphocytes

Regulatory T Cells Selectively Preserve Immune Privilege of Self-Antigens during Viral Central Nervous System Infection

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Suppression of CD4⁺Effector Responses by Naturally Occurring CD4⁺CD25⁺Foxp3⁺Regulatory T Cells Contributes to Experimental Cerebral Malaria

Suppression of CD4⁺Effector Responses by Naturally Occurring CD4⁺CD25⁺Foxp3⁺Regulatory T Cells Contributes to Experimental Cerebral Malaria

Modulation of the Immune and Inflammatory Responses by Plasmodium falciparum Schizont Extracts: Role of Myeloid Dendritic Cells in Effector and Regulatory Functions of CD4 ⁺ Lymphocytes