IFNγ-induction of TH1-like regulatory T cells controls antiviral responses

Gocher-Demske, Angela M; Cui, Jian; Szymczak-Workman, Andrea L.; Vignali, Kate M.; Latini, Julianna N.; Pieklo, Gwen P.; Kimball, Jesse C.; Avery, Lyndsay; Cipolla, Ellyse; Huckestein, Brydie R.; Hedden, Lee; Meisel, Marlies; Alcorn, John F.; Kane, Larry; Workman, Creg J.; Vignali, Dario A.A.

doi:10.1038/s41590-023-01453-w

Cited by 26 publications

(16 citation statements)

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“…Although we cannot rule this out, we conclude that any effects anti-IFNγ treatment had on Th1-like iTreg proliferation were subtle and not detected except at high Tsupp : Tresp ratios (1:20). Alternatively, inhibiting access to IFNγ during the polarization process may have impacted Th1-like suppressive capabilities in other ways ( 31 ). Collectively, our data show that compared to Tregs not exposed to IL-12 early during their polarization process, Th1-like iTregs exhibit superior suppressive activity and more robust proliferation in in vitro suppression assays, and these effects may in part be conveyed through IFNγ produced by Th1-like iTregs during their differentiation process.…”

Section: Resultsmentioning

confidence: 99%

“…These cells often exhibit reduced suppressive capacities compared to Treg cells from healthy individuals ( 47 ). While some reports indicate these Th1-like iTregs may contribute to disease progression by promoting inflammation or loss of immune tolerance ( 46 ), other studies propose that they might represent a compensatory response aimed at controlling excessive immune activation ( 31 , 48 ). The precise mechanisms underlying the functional changes observed in Th1-like iTregs during autoimmunity are still unclear, and it is likely that the inflammatory microenvironment within affected tissues influences Th1-like iTreg differentiation and function.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study, Gocher-Demske et al., showed that Th1-like iTregs could detect inflammatory signals, exert regulatory control over immune responses, prevent prolonged immunoinflammatory reactions, and influence the quality and quantity of memory T-cell responses during acute and chronic viral infections ( 31 ). In our in vivo study using a Th1-mediated mouse model of AA, therapeutically administering Th1-like iTregs improved clinical scores and extended survival.…”

Section: Discussionmentioning

confidence: 99%

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PRMT5 regulates epigenetic changes in suppressive Th1-like iTregs in response to IL-12 treatment

Jadon,

Shanthalingam,

Tew

et al. 2024

Front. Immunol.

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BackgroundInduced regulatory T cells (iTregs) are a heterogeneous population of immunosuppressive T cells with therapeutic potential. Treg cells show a range of plasticity and can acquire T effector-like capacities, as is the case for T helper 1 (Th1)-like iTregs. Thus, it is important to distinguish between functional plasticity and lineage instability. Aplastic anemia (AA) is an autoimmune disorder characterized by immune-mediated destruction of hematopoietic stem and progenitor cells in the bone marrow (BM). Th1-like 1 iTregs can be potent suppressors of aberrant Th1-mediated immune responses such as those that drive AA disease progression. Here we investigated the function of the epigenetic enzyme, protein arginine methyltransferase 5 (PRMT5), its regulation of the iTreg-destabilizing deacetylase, sirtuin 1 (Sirt1) in suppressive Th1-like iTregs, and the potential for administering Th1-like iTregs as a cell-based therapy for AA.MethodsWe generated Th1-like iTregs by culturing iTregs with IL-12, then assessed their suppressive capacity, expression of iTreg suppression markers, and enzymatic activity of PRMT5 using histone symmetric arginine di-methylation (H3R2me2s) as a read out. We used ChIP sequencing on Th1 cells, iTregs, and Th1-like iTregs to identify H3R2me2s-bound genes unique to Th1-like iTregs, then validated targets using CHiP-qPCR. We knocked down PRMT5 to validate its contribution to Th1-like iTreg lineage commitment. Finally we tested the therapeutic potential of Th1-like iTregs using a Th1-mediated mouse model of AA.ResultsExposing iTregs to the Th1 cytokine, interleukin-12 (IL-12), during early events of differentiation conveyed increased suppressive function. We observed increased PRMT5 enzymatic activity, as measured by H3R2me2s, in Th1-like iTregs, which was downregulated in iTregs. Using ChIP-sequencing we discovered that H3R2me2s is abundantly bound to the Sirt1 promoter region in Th1-like iTregs to negatively regulate its expression. Furthermore, administering Th1-like iTregs to AA mice provided a survival benefit.ConclusionsKnocking down PRMT5 in Th1-like iTregs concomitantly reduced their suppressive capacity, supporting the notion that PRMT5 is important for the superior suppressive capacity and stability of Th1-like iTregs. Conclusively, therapeutic administration of Th1-like iTregs in a mouse model of AA significantly extended their survival and they may have therapeutic potential.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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PRMT5 regulates epigenetic changes in suppressive Th1-like iTregs in response to IL-12 treatment

Jadon,

Shanthalingam,

Tew

et al. 2024

Front. Immunol.

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“…24–48 h; see above). For comparison, during acute infection with lymphocytic choriomeningitis virus or influenza A virus and resulting elevation of IFNγ levels in mice, Tregs acquire already within a week a Th1‐like phenotype that limits CD8 + T‐cell effector function, proliferation and memory formation [95]. It is thus tempting to speculate how, in the case of YF17D, a uniquely postponed and abbreviated Treg‐cell response may favour the fast activation and robust expansion of a vigorous antiviral cellular immunity.…”

Section: Original Immune Responses To Yf17d – Leveraging For Its Use ...mentioning

confidence: 99%

YF17D‐based vaccines – standing on the shoulders of a giant

Sanchez‐Felipe,

Alpizar,

et al. 2024

Eur J Immunol

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SummaryLive‐attenuated yellow fever vaccine (YF17D) was developed in the 1930s as the first ever empirically derived human vaccine. Ninety years later, it is still a benchmark for vaccines made today. YF17D triggers a particularly broad and polyfunctional response engaging multiple arms of innate, humoral and cellular immunity. This unique immunogenicity translates into an extraordinary vaccine efficacy and outstanding longevity of protection, possibly by single‐dose immunization. More recently, progress in molecular virology and synthetic biology allowed engineering of YF17D as a powerful vector and promising platform for the development of novel recombinant live vaccines, including two licensed vaccines against Japanese encephalitis and dengue, even in paediatric use. Likewise, numerous chimeric and transgenic preclinical candidates have been described. These include prophylactic vaccines against emerging viral infections (e.g. Lassa, Zika and SARS‐CoV‐2) and parasitic diseases (e.g. malaria), as well as therapeutic applications targeting persistent infections (e.g. HIV and chronic hepatitis), and cancer. Efforts to overcome historical safety concerns and manufacturing challenges are ongoing and pave the way for wider use of YF17D‐based vaccines. In this review, we summarize recent insights regarding YF17D as vaccine platform, and how YF17D‐based vaccines may complement as well as differentiate from other emerging modalities in response to unmet medical needs and for pandemic preparedness.

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“…Indeed, the Treg compartment exhibits a degree of plasticity that enables Tregs to modulate their suppressive functions according to the surrounding microenvironment. For example, interferon gamma (IFN-γ) or IL-27 induce Th1-Tregs with expression of Th1-related molecules, namely chemokine (C-X-C motif) receptor 3 (CXCR3) and T-box gene expressed in T cells (T-bet) ( 35 ), which can migrate to sites of Th1 inflammation and suppress Th1 cells effectively ( 36 ). Th2-specific Tregs are tailored to suppress Th2 responses, which are associated with allergic inflammation and characterized by Th2 cytokines like IL-4, IL-5, and IL-13, as well as GATA binding protein 3(GATA3) ( 37 , 38 ).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Treg cells by cytokine signaling and co-stimulatory molecules

Zong,

Deng,

Chong

2024

Front. Immunol.

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CD4+CD25+Foxp3+ regulatory T cells (Tregs), a vital component of the immune system, are responsible for maintaining immune homeostasis and preventing excessive immune responses. This review explores the signaling pathways of the cytokines that regulate Treg cells, including transforming growth factor beta (TGF-β), interleukin (IL)-2, IL-10, and IL-35, which foster the differentiation and enhance the immunosuppressive capabilities of Tregs. It also examines how, conversely, signals mediated by IL-6 and tumor necrosis factor -alpha (TNF-α) can undermine Treg suppressive functions or even drive their reprogramming into effector T cells. The B7 family comprises indispensable co-stimulators for T cell activation. Among its members, this review focuses on the capacity of CTLA-4 and PD-1 to regulate the differentiation, function, and survival of Tregs. As Tregs play an essential role in maintaining immune homeostasis, their dysfunction contributes to the pathogenesis of autoimmune diseases. This review delves into the potential of employing Treg-based immunotherapy for the treatment of autoimmune diseases, transplant rejection, and cancer. By shedding light on these topics, this article aims to enhance our understanding of the regulation of Tregs by cytokines and their therapeutic potential for various pathological conditions.

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IFNγ-induction of TH1-like regulatory T cells controls antiviral responses

Cited by 26 publications

References 68 publications

PRMT5 regulates epigenetic changes in suppressive Th1-like iTregs in response to IL-12 treatment

PRMT5 regulates epigenetic changes in suppressive Th1-like iTregs in response to IL-12 treatment

YF17D‐based vaccines – standing on the shoulders of a giant

Regulation of Treg cells by cytokine signaling and co-stimulatory molecules

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