Induction of regulatory T-cells from memory T-cells is perturbed during acute exacerbation of multiple sclerosis

Mohiuddin, Imran H.; Pillai, Vinodh; Baughman, Ethan; Greenberg, Benjamin; Frohman, Elliot M.; Crawford, Michael P.; Sinha, Sushmita; Karandikar, Nitin J.

doi:10.1016/j.clim.2016.05.001

Cited by 7 publications

(4 citation statements)

References 44 publications

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“…Conditions were based on previous publications (22)(23)(24) and included: 1) Media Alone/Th0: no cytokines/antibodies added; 2) Th1: anti-IL-4 7 μg/mL BD554481, IL-2 10 ng/mL BD554603, IL-12 10 ng/mL BD554613; 3) Th2: anti-IFNγ 7 μg/mL BD554698, IL-2 10 ng/mL, IL-4 10 ng/mL BD554605; 4) Th17: anti-IL4 7 μg/mL, anti-IFNγ 7 μg/mL, TGFβ1 10 ng/mL eBioscience 14-8348-62, IL-1β 10 ng/mL BD554602, IL-6 50 ng/mL BD550071. Cultures were activated with 1 μg/mL each of fixed anti-CD3 (eBioscience, 16-0037-85) and anti-CD28 (eBioscience, 16-0289-85), as described previously (40) and incubated for 7 d at 37°C. Supernatants were aliquoted at day 7 for enzyme-linked immunosorbent assays (ELISAs), and cells were washed twice with phosphate-buffered saline (PBS) for suppression assay cultures.…”

Section: Methodsmentioning

confidence: 99%

CD4 T cell-intrinsic role for the T helper 17 signature cytokine IL-17: Effector resistance to immune suppression

Crawford

Sinha

Renavikar

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Untoward effector CD4+ T cell responses are kept in check by immune regulatory mechanisms mediated by CD4+ and CD8+ T cells. CD4+ T helper 17 (Th17) cells, characterized by IL-17 production, play important roles in the pathogenesis of autoimmune diseases (such as arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, among others) and in the host response to infection and cancer. Here, we demonstrate that human CD4+ T cells cells exposed to a Th17-differentiating milieu are significantly more resistant to immune suppression by CD8+ T cells compared to control Th0 cells. This resistance is mediated, in part, through the action of IL-17A, IL-17F, and IL-17AF heterodimer through their receptors (IL-17RA and IL-17RC) on CD4+ T cells themselves, but not through their action on CD8+ T cells or APC. We further show that IL-17 can directly act on non-Th17 effector CD4+ T cells to induce suppressive resistance, and this resistance can be reversed by blockade of IL-1β, IL-6, or STAT3. These studies reveal a role for IL-17 cytokines in mediating CD4-intrinsic immune resistance. The pathways induced in this process may serve as a critical target for future investigation and immunotherapeutic intervention.

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Section: Methodsmentioning

confidence: 99%

CD4 T cell-intrinsic role for the T helper 17 signature cytokine IL-17: Effector resistance to immune suppression

Crawford

Sinha

Renavikar

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Of note, Tregs are scarce in MS brain lesions [ 97 ] whereas in EAE, they proliferate into the CNS [ 173 ]. CD4 + Tregs expressing the transcription factor Foxp3 is required for peripheral immunological tolerance (regulation of autoreactive immune cells) [ 192 ]; deletion of Foxp3 on CD4 + regulatory cells leads to multiorgan autoimmunity [ 162 ] and malfunction of Tregs are related to the alteration of the Foxp3 gene.…”

Section: Treg Cellsmentioning

confidence: 99%

The Plasticity of Immune Cell Response Complicates Dissecting the Underlying Pathology of Multiple Sclerosis

Sarkar,

Willson,

Jordan

2024

Journal of Immunology Research

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Multiple sclerosis (MS) is a neurodegenerative autoimmune disease characterized by the destruction of the myelin sheath of the neuronal axon in the central nervous system. Many risk factors, including environmental, epigenetic, genetic, and lifestyle factors, are responsible for the development of MS. It has long been thought that only adaptive immune cells, especially autoreactive T cells, are responsible for the pathophysiology; however, recent evidence has indicated that innate immune cells are also highly involved in disease initiation and progression. Here, we compile the available data regarding the role immune cells play in MS, drawn from both human and animal research. While T and B lymphocytes, chiefly enhance MS pathology, regulatory T cells (Tregs) may serve a more protective role, as can B cells, depending on context and location. Cells chiefly involved in innate immunity, including macrophages, microglia, astrocytes, dendritic cells, natural killer (NK) cells, eosinophils, and mast cells, play varied roles. In addition, there is evidence regarding the involvement of innate-like immune cells, such as γδ T cells, NKT cells, MAIT cells, and innate-like B cells as crucial contributors to MS pathophysiology. It is unclear which of these cell subsets are involved in the onset or progression of disease or in protective mechanisms due to their plastic nature, which can change their properties and functions depending on microenvironmental exposure and the response of neural networks in damage control. This highlights the need for a multipronged approach, combining stringently designed clinical data with carefully controlled in vitro and in vivo research findings, to identify the underlying mechanisms so that more effective therapeutics can be developed.

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“…The 24 multiwell tissue culture plates (Costar Ref 3413, tissue culture treated polystyrene with 6.55 mm insert and 0.4 micrometer polycarbonate membranes) were plated with 1 μg/ml each of anti-CD3 and anti-CD28, as previously described [12]. Anti-CD3/anti-CD28 1ug/ml was fixed per manufacturer protocol to Sperotech polystyrene protein G particles (cat PGP-60-05, 0.5 w/v, 6.8 um) and were used within the well insert for stimulation.…”

Section: Transwell Exogenous Il-17 Addition Suppression Assaysmentioning

confidence: 99%

IL-17 cytokines preferentially act on naïve CD4+ T cells with the IL-17AF heterodimer inducing the greatest functional changes

2023

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CD4+ T-helper 17 (Th17) T cells are a key population in protective immunity during infection and in self-tolerance/autoimmunity. Through the secretion of IL-17, Th17 cells act in promotion of inflammation and are thus a major potential therapeutic target in autoimmune disorders. Recent reports have brought to light that the IL-17 family cytokines, IL-17A, IL-17F and IL-17AF, can directly act on CD4+ T-cells, both in murine and human systems, inducing functional changes in these cells. Here we show that this action is preferentially targeted toward naïve, but not memory, CD4+ T-cells. Naïve cells showed transcriptome changes as early as 48 hours post-IL-17 exposure, whereas memory cells remained unaffected as late as 7 days. These functional differences occurred despite similar IL-17 receptor expression on these subsets and were maintained in co-culture/transwell systems, with each subset maintaining its functional response to IL-17. Importantly, there were differences in downstream transcriptional signaling by the three IL-17 cytokines, with the IL-17AF heterodimer conferring both the greatest transcriptional change and most altered functional consequences. Detailed transcriptome analysis provides important insights into the genes and pathways that are modulated as a result of IL-17-mediated signaling and may serve as targets of future therapies.

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Induction of regulatory T-cells from memory T-cells is perturbed during acute exacerbation of multiple sclerosis

Cited by 7 publications

References 44 publications

CD4 T cell-intrinsic role for the T helper 17 signature cytokine IL-17: Effector resistance to immune suppression

CD4 T cell-intrinsic role for the T helper 17 signature cytokine IL-17: Effector resistance to immune suppression

The Plasticity of Immune Cell Response Complicates Dissecting the Underlying Pathology of Multiple Sclerosis

IL-17 cytokines preferentially act on naïve CD4+ T cells with the IL-17AF heterodimer inducing the greatest functional changes

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