Dysfunction of IL-10-producing type 1 regulatory T cells and CD4+CD25+ regulatory T cells in a mimic model of human multiple sclerosis in Cynomolgus monkeys

Ma, Anlun; Xiong, Zhenggang; Hu, Yanxin; Qi, Shijie; Song, Lijun; Dun, Hao; Zhang, Liangyan; Lou, Deyan; Yang, Peng; Zhao, Zhongpeng; Wang, Xiliang; Zhang, Dongqing; Daloze, Pierre; Chen, Huifang

doi:10.1016/j.intimp.2009.01.034

Cited by 45 publications

(50 citation statements)

References 40 publications

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“…Indeed, this study showed MSCs conferring immune protection through the generation of FoxP3 + T regs . This T cell subset is known for its anti-inflammatory and immunosuppressive roles, including the suppression of autoimmunity (39,40).…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

Patel

Meyer

Greco

et al. 2010

The Journal of Immunology

358

291

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Mesenchymal stem cells (MSCs) have been shown to support breast cancer growth. Because MSCs also increase the frequency of regulatory T cells (Tregs), this study tested the hypothesis that human MSCs, via Tregs, protect breast cancer cells (BCCs) from immune clearance MSCs suppressed the proliferation of PBMCs when the latter were exposed to gamma-irradiated BCCs. Similarly, MSCs showed significant inhibition of PBMC migration toward BCCs and a corresponding decrease in CXCL12. MSCs also inhibited NK cell and CTL functions, which correlated with reduced numbers of CD8+ and CD56+ cells compared with parallel cultures without MSCs. The reduced NK and CTL activities correlated with a decrease in intracellular and secreted granzyme B. To explain these immunosuppressive findings, we compared Treg levels after coculture with MSCs and found an ∼2-fold increase in Tregs, with associated decreases in antitumor Th1 cytokines and increases in Th2 cytokines. MSC-derived TGF-β1 was largely responsible for the increase in Tregs based on knockdown studies. In the presence of Treg depletion, PBMC proliferation and effector functions were partially restored. Together, these studies show an MSC-mediated increase in Tregs in cocultures of PBMCs and BCCs. The results could be explained, in part, by the increase in Th2-type cytokines and MSC-generated TGF-β1. These findings demonstrate immune protection by MSCs to BCCs. The reduction in immune cell proliferation and recruitment mediated by MSCs has implications for treatment of breast cancer with chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

Patel

Meyer

Greco

et al. 2010

The Journal of Immunology

358

291

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“…A recent report by Astier et al established a connection between defects in the CD46-mediated induction of IL-10 in CD4 ϩ T cells with multiple sclerosis (MS), which suggests that CD46 may indeed play a role in the prevention of autoimmunity in humans (3,32). Similarly, dysfunctional CD46-mediated IL-10 production in T cells has now been connected with acute experimental autoimmune encephalomyelitis (EAE) in cynomolgus monkeys (which express CD46 naturally) (30).…”

Section: Discussionmentioning

confidence: 99%

CD46 Engagement on Human CD4⁺T Cells Produces T Regulatory Type 1-Like Regulation of Antimycobacterial T Cell Responses

Truscott¹,

Abate

Price

et al. 2010

Infect Immun

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Understanding the regulation of human immune responses is critical for vaccine development and treating infectious diseases. We have previously shown that simultaneous engagement of the T cell receptor (TCR) and complement regulator CD46 on human CD4؉ T cells in the presence of interleukin-2 (IL-2) induces potent secretion of the immunomodulatory cytokine IL-10. These T cells mediate IL-10-dependent suppression of bystander CD4؉ T cells activated in vitro with anti-CD3 and anti-CD28 costimulation, reflecting a T regulatory type 1 (Tr1)-like phenotype. However, CD46-mediated negative regulation of pathogen-specific T cells has not been described. Therefore, we studied the ability of CD46-activated human CD4؉ T cells to suppress T cell responses to Mycobacterium bovis BCG, the live vaccine that provides infants protection against the major human pathogen Mycobacterium tuberculosis. Our results demonstrate that soluble factors secreted by CD46-activated human CD4؉ T cells suppress mycobacterium-specific CD4 ؉ , CD8 ؉ , and ␥ 9 ␦ 2 TCR ؉ T cells. Dendritic cell functions were not downregulated in our experiments, indicating that CD46-triggered factors directly suppress pathogen-specific T cells. Interestingly, IL-10 appeared to play a less pronounced role in our system, especially in the suppression of ␥ 9 ␦ 2 TCR ؉ T cells, suggesting the presence of additional undiscovered soluble immunoregulatory factors. Blocking endogenous CD46 signaling 3 days after mycobacterial infection enhanced BCG-specific T cell responses in a subset of volunteers. Taken together, these results indicate that CD46-dependent negative regulatory mechanisms can impair T cell responses vital for immune defense against mycobacteria. Therefore, modulating CD46-induced immune regulation could be integral to the development of improved tuberculosis therapeutics or vaccines.

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“…Recently, CD46 was shown to be a receptor for Jagged-1 and CD46 activation induced a switch from inflammatory IFN-γ release to IL-10 expression by Tregs [161]. The role of CD46 in MS has been well documented, additionally, an experiment with cyanomolgus monkeys having MS-like disease revealed a tenfold reduction in CD46-mediated IL-10 expression [162, 163]. CD46 also enhances CD25 expression and elevates granzyme B production [164].…”

Section: Main Textmentioning

confidence: 99%

Regulatory T cells in multiple sclerosis and myasthenia gravis

Danikowski

Jayaraman

Prabhakar

2017

J Neuroinflammation

262

171

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Multiple sclerosis (MS) is a chronic debilitating disease of the central nervous system primarily mediated by T lymphocytes with specificity to neuronal antigens in genetically susceptible individuals. On the other hand, myasthenia gravis (MG) primarily involves destruction of the neuromuscular junction by antibodies specific to the acetylcholine receptor. Both autoimmune diseases are thought to result from loss of self-tolerance, which allows for the development and function of autoreactive lymphocytes. Although the mechanisms underlying compromised self-tolerance in these and other autoimmune diseases have not been fully elucidated, one possibility is numerical, functional, and/or migratory deficits in T regulatory cells (Tregs). Tregs are thought to play a critical role in the maintenance of peripheral immune tolerance. It is believed that Tregs function by suppressing the effector CD4+ T cell subsets that mediate autoimmune responses. Dysregulation of suppressive and migratory markers on Tregs have been linked to the pathogenesis of both MS and MG. For example, genetic abnormalities have been found in Treg suppressive markers CTLA-4 and CD25, while others have shown a decreased expression of FoxP3 and IL-10. Furthermore, elevated levels of pro-inflammatory cytokines such as IL-6, IL-17, and IFN-γ secreted by T effectors have been noted in MS and MG patients. This review provides several strategies of treatment which have been shown to be effective or are proposed as potential therapies to restore the function of various Treg subsets including Tr1, iTr35, nTregs, and iTregs. Strategies focusing on enhancing the Treg function find importance in cytokines TGF-β, IDO, interleukins 10, 27, and 35, and ligands Jagged-1 and OX40L. Likewise, strategies which affect Treg migration involve chemokines CCL17 and CXCL11. In pre-clinical animal models of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune myasthenia gravis (EAMG), several strategies have been shown to ameliorate the disease and thus appear promising for treating patients with MS or MG.

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Dysfunction of IL-10-producing type 1 regulatory T cells and CD4+CD25+ regulatory T cells in a mimic model of human multiple sclerosis in Cynomolgus monkeys

Cited by 45 publications

References 40 publications

Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

CD46 Engagement on Human CD4⁺T Cells Produces T Regulatory Type 1-Like Regulation of Antimycobacterial T Cell Responses

Regulatory T cells in multiple sclerosis and myasthenia gravis

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Dysfunction of IL-10-producing type 1 regulatory T cells and CD4+CD25+ regulatory T cells in a mimic model of human multiple sclerosis in Cynomolgus monkeys

Cited by 45 publications

References 40 publications

Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

CD46 Engagement on Human CD4+T Cells Produces T Regulatory Type 1-Like Regulation of Antimycobacterial T Cell Responses

Regulatory T cells in multiple sclerosis and myasthenia gravis

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CD46 Engagement on Human CD4⁺T Cells Produces T Regulatory Type 1-Like Regulation of Antimycobacterial T Cell Responses