FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway

  title={FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway},
  author={Achilles Ntranos and Olivia J Hall and Dionne P. Robinson and Inna V. Grishkan and Jason T. Schott and Dominique M Tosi and Sabra L. Klein and Peter A. Calabresi and Anne R. Gocke},
  journal={Journal of Neuroimmunology},

Figures from this paper

Identification of a novel mechanism of action of fingolimod (FTY720) on human effector T cell function through TCF-1 upregulation

The results reveal a previously unknown mechanism of the effect of FTY720 on human CD4+ T cell modulation in multiple sclerosis and demonstrate the role of TCF-1 in human T cell activation and effector function.

S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission

It is demonstrated that recipient sphingosine kinase 1 (Sphk1), but not Sphk2, was required for optimal S1PR1-dependent donor T-cell allogeneic responses by secreting S1P, which validates Sphk1 or S1 PR1 as a therapeutic target for the prevention of GVHD and leukemia relapse.

Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways

Data suggest that FTY720 mediated inhibition of TCA is due to inhibition of distal TCR signaling, which may aid in developing novel FTY 720-based immunomodulatory agents.

Fingolimod retains cytolytic T cells and limits T follicular helper cell infection in lymphoid sites of SIV persistence

The FTY720-induced inhibition of T cell egress from LN resulted in a measurable decrease of SIV-DNA content in blood as well as in LN Tfh cells in most treated animals, providing rationale for strategies to retain antiviral T cells in lymphoid tissues to target HIV remission.

Fingolimod targeting protein phosphatase 2A differently affects IL‐33 induced IL‐2 and IFN‐γ production in CD8+ lymphocytes

These findings directly improve the understanding of FTY720 therapy in MS and could also contribute to side effects of F TY720 treatment, like progressive multifocal leukoencephalopathy, caused by an insufficient immune response to a viral infection.

Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis

M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod, and was found to be an important and specific parameter to distinguish EAE mice prone to better fingolIMod efficacy.

FTY720 ameliorates GvHD by blocking T lymphocyte migration to target organs and by skin fibrosis inhibition

The results suggest that FTY720 prevents GvHD progression via immunosuppression of TH17 and simultaneously acts an anti-fibrotic agent.

Adaptive Immune Responses in a Multiple Sclerosis Patient with Acute Varicella-Zoster Virus Reactivation during Treatment with Fingolimod

The dynamics of systemic and intrathecal immune responses associated with symptomatic VZV reactivation including cessation of fingolimod and initiation of antiviral therapy are studied.

Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential

Previous findings and new discoveries about the importance of S1P and S1PR signaling in the recruitment of immune cells and lymphocyte retention in inflamed tissues are summarized.



FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration.

Results indicate that FTY 720 exhibits not only a prophylactic but also a therapeutic effect on EAE in rats and mice, and that the effect of FTY720 appears to be due to a reduction of the infiltration of myelin antigen-specific CD4(+) T cells into the inflammation site.

Sphingosine Kinase 2 Is Required for Modulation of Lymphocyte Traffic by FTY720*

Although FTY720 was selectively activated in vivo by SPHK2, other S1P pro-drugs can be phosphorylated to cause lymphopenia through the action of additional sphingosine kinases.

FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system

FTY720 may act through immune‐based and central mechanisms to reduce inflammation and support structural restoration of the central nervous system parenchyma and short‐term, low‐dose administration of FTY720 could help treat chronic (viral) infections.

IL-2 Regulates Perforin and Granzyme Gene Expression in CD8+ T Cells Independently of Its Effects on Survival and Proliferation1

It is shown that IL-2 increased the expression of perforin and granzyme A, B, and C mRNA; intracellular granzyme B protein levels; and cytolytic function in a dose-dependent manner during primary activation of murine CD8+ T cells in vitro.

Myelin Antigen-Specific CD8+ T Cells Are Encephalitogenic and Produce Severe Disease in C57BL/6 Mice1

It is reported that synthetic peptides 35–55 from myelin oligodendrocyte glycoprotein (pMOG35–55) consistently activate a high proportion of CD8+ αβTCR+ T cells that are encephalitogenic in C57BL/6 (B6) mice.

Pathogenic CD8 T Cells in Multiple Sclerosis and Its Experimental Models

Understanding how CNS-reactive CD8 T cells escape tolerance induction and induce CNS autoimmunity is critical to the ability to propose and test new therapies for MS.

Kv1.3 Deletion Biases T Cells toward an Immunoregulatory Phenotype and Renders Mice Resistant to Autoimmune Encephalomyelitis

Skewing of CD4+ T cell differentiation toward Ag-specific regulatory T cells by pharmacological blockade or genetic suppression of Kv1.3 might be beneficial for therapy of immune-mediated diseases such as multiple sclerosis.

Phosphorylation of the Immunomodulatory Drug FTY720 by Sphingosine Kinases*

It is found that, while FTY720 is also phosphorylated by human SPHK1, the human type 2 isoform phosphorylates the drug 30-fold more efficiently, because of a lower Km of FTY 720 for SPHK2.