Tim3+ Foxp3 + Treg Cells Are Potent Inhibitors of Effector T Cells and Are Suppressed in Rheumatoid Arthritis

Sun, Huaqiang; Gao, Wenwu; Pan, Wenping; Zhang, Qian; Wang, Gongteng; Feng, Dapeng; Geng, Xiubin; Yan, Xinfeng; Li, Shufeng

doi:10.1007/s10753-017-0577-6

Cited by 47 publications

(26 citation statements)

References 27 publications

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“…Finally, Fingolimod addition to activated T cell cultures in vitro did not affect per se the frequency of IL-17-secreting cells [63], suggesting that the inhibition of IL-17 secretion by T cells in patients with relapsing-remitting multiple sclerosis might be an indirect effect on another cell population. been associated with superior suppressive capacity [48,53], and we observed that Fingolimod increased significantly the expression of Tim-3 on Tregs from patients, suggesting that these cells also regained suppressive capacities. In agreement with this, Fingolimod has been shown to inhibit the PI3K/AKT signaling pathway [58,67], which is activated in Tregs from relapsingremitting multiple sclerosis patients and contributes to the Th1-like phenotype and defect in suppression as compared to healthy individuals [17,32].…”

Section: Discussionmentioning

confidence: 57%

Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo

Dominguez‐Villar

Raddassi

Danielsen

et al. 2019

Journal of Autoimmunity

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Fingolimod is an approved therapeutic option for patients with relapsing-remitting multiple sclerosis that primarily functions by sequestering T cells in lymph nodes inhibiting their egress to the central nervous system. However, recent data suggests that Fingolimod may also directly affect the immune cell function. Here we examined the in vivo effects of Fingolimod in modulating the phenotype and function of T cell and Foxp3 regulatory T cell populations in patients with multiple sclerosis under Fingolimod treatment. Besides decreasing the cell numbers in peripheral blood and sera levels of pro-inflammatory cytokines, Fingolimod inhibited the expression of Th1 and Th17 cytokines on CD4 T cells and increased the expression of exhaustion markers. Furthermore, treatment increased the frequency of regulatory T cells in blood and inhibited the Th1-like phenotype that is characteristic of patients with multiple sclerosis, augmenting the expression of markers associated with increased suppressive function. Overall, our data suggest that Fingolimod performs other important immunomodulatory functions besides altering T cell migratory capacities, with consequences for other autoimmune pathologies characterized by excessive Th1/Th17 responses and Th1-like regulatory T cell effector phenotypes.

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Section: Discussionmentioning

confidence: 57%

Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo

Dominguez‐Villar

Raddassi

Danielsen

et al. 2019

Journal of Autoimmunity

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“…Recent evidence has demonstrated that TIM3/Gal9 is an important inhibitory pathway in the immune response of cancer [ 29 ]. TIM3 has been proved to be expressed on multiple immune cells, and blocking TIM3/Gal9 has an effect on various immune cells, such as effector T cells, Tregs, macrophages and monocytes [ 20 , 22 , 30 , 31 ]. Our previous study has identified the overexpression of TIM3 in HNSCC patients and the association of TIM3 expression with MDSCs [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

“…While blockade of TIM3 could promote IFN-γ-mediated antitumor immunity of T cells [ 21 ]. A research showed that TIM3 was expressed on Tregs and correlated with rheumatoid arthritis activity [ 22 ]. An in vitro experiment suggested that TIM3 on Tregs was correlated with tumor size of ovarian carcinoma [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Blockade of TIM3 relieves immunosuppression through reducing regulatory T cells in head and neck cancer

Liu

Yang

et al. 2018

J Exp Clin Cancer Res

101

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BackgroundT-cell immunoglobulin mucin 3 (TIM3) is a negative immune checkpoint and plays a crucial part in tumor-induced immune suppression. However, the mechanism of TIM3 in regulating immunosuppression in head and neck squamous cell carcinoma (HNSCC) was still not quite clear.MethodsWe carried out the immunohistochemistry staining of HNSCC tissue microarrays. Through quantification of the histoscore, we performed the correlation analysis among the TIM3, Galectin-9, Foxp3, CD68 and CD163. The effects of TIM3 on regulatory T cells (Tregs) and macrophages were detected by utilizing the Tgfbr1/Pten 2cKO HNSCC mouse model. Flow cytometry were used to analysis the percent of Tregs, macrophages and IFN-γ.ResultsWe demonstrated the close association among TIM3/Galectin-9 pathway, regulatory T cell marker (Foxp3) and macrophage marker (CD68, CD163) in human HNSCC. In the transgenic HNSCC mouse model, blockade of TIM3 by the anti-TIM3 monoclonal antibody induced a reduction of CD4+CD25+Foxp3+ Tregs. Meanwhile, the population of TIM3+ Tregs was also decreased. However, the population of CD206+ macrophages was not significantly declined. The increased IFN-γ production on CD8+ T cells in anti-TIM3 treatment mice showed that the antitumor immune response was enhanced through suppression of these negative immune factors.ConclusionsThe present study demonstrated that TIM3 was associated with the immunosuppression in HNSCC. And targeting TIM3 can enhance anti-tumor immune response by decreasing Tregs in HNSCC.

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“…Tim-3 is considered to play an important role in immune tolerance as a negative regulator of proinflammatory responses to avoid excessive host damage [ 86 ]. Of note, Tim-3 + Foxp3 + Tregs display a higher suppressive function than Tim3 − Foxp3 + Tregs [ 87 ]. Tim-3 is also involved in mediating T-cell exhaustion during cancer and chronic viral infections [ 88 , 89 ].…”

Section: T-cell Immunoglobulin and Mucin Domain 3 (Tim-3)mentioning

confidence: 99%

Control of NK Cell Activation by Immune Checkpoint Molecules

Beldi‐Ferchiou

Caillat‐Zucman

2017

IJMS

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The development of cancer and chronic infections is facilitated by many subversion mechanisms, among which enhanced expression of immune checkpoints molecules, such as programmed death-1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on exhausted T cells. Recently, immune checkpoint inhibitors have shown remarkable efficiency in the treatment of a number of cancers. However, expression of immune checkpoints on natural killer (NK) cells and its functional consequences on NK cell effector functions are much less explored. In this review, we focus on the current knowledge on expression of various immune checkpoints in NK cells, how it can alter NK cell-mediated cytotoxicity and cytokine production. Dissecting the role of these inhibitory mechanisms in NK cells is critical for the full understanding of the mode of action of immunotherapies using checkpoint inhibitors in the treatment of cancers and chronic infections.

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Tim3+ Foxp3 + Treg Cells Are Potent Inhibitors of Effector T Cells and Are Suppressed in Rheumatoid Arthritis

Cited by 47 publications

References 27 publications

Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo

Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo

Blockade of TIM3 relieves immunosuppression through reducing regulatory T cells in head and neck cancer

Control of NK Cell Activation by Immune Checkpoint Molecules

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