Modulation of Tregs and iNKT by Fingolimod in Multiple Sclerosis Patients.

Diana Ferraro,Andrea Cossarizza,Stefano Meletti,Patrizia Sola,Marcello Pinti,Marco Fogliani,Riccardo Orlandi,Francesca Vitetta,Anna Maria Simone,Milena Nasi,Sara De Biasi

doi:10.3390/cells10123324

Diana Ferraro, Andrea Cossarizza + Show 9 more

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https://doi.org/10.3390/cells10123324

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Abstract

The altered numbers and functions of cells belonging to immunoregulatory cell networks such as T regulatory (Tregs) and invariant Natural Killer T (iNKT) cells have been reported in Multiple Sclerosis (MS), an immune-mediated disease. We aimed to assess the frequencies of Tregs and iNKT cells in MS patients throughout a one-year treatment with fingolimod (FTY) and to correlate immunological data with efficacy and safety data. The percentage of Tregs (defined as Live Dead-CD3 + CD4 + FoxP3 + CD25++/CD127− cells) increased steadily throughout the year, while there was no significant difference in the absolute number or percentage of iNKT cells (defined as CD3 + CD14−CD19− Vα24-Jα18 TCR+ cells). However, out of all the iNKT cells, the CD8+ iNKT and CD4−CD8− double-negative (DN) cell percentages steadily increased, while the CD4+ iNKT cell percentages decreased significantly. The mean percentage of CD8+ T cells at all time-points was lower in patients with infections throughout the study. The numbers and percentages of DN iNKT cells were more elevated, considering all time-points, in patients who presented a clinical relapse. FTY may, therefore, exert its beneficial effect in MS patients through various mechanisms, including the increase in Tregs and in iNKT subsets with immunomodulatory potential such as CD8+ iNKT cells. The occurrence of infections was associated with lower mean CD8+ cell counts during treatment with FTY.

Highlights

Multiple Sclerosis (MS) is considered an immune-mediated disease, characterized by the activation of lymphocytes directed against central nervous system autoantigens
The altered numbers and functions of cells belonging to immunoregulatory cell networks such as T regulatory (Tregs) and invariant Natural Killer T cells have been reported in MS [1,2,3,4,5,6,7,8,9]
Reduced numbers of invariant Natural Killer T (iNKT) or anergy of iNKT cells have been described in MS patients [5,6,7], with a significant increase following a treatment with beta-interferon, suggesting a protective role of iNKT cells in MS [15]

Summary

Introduction

Multiple Sclerosis (MS) is considered an immune-mediated disease, characterized by the activation of lymphocytes directed against central nervous system autoantigens. Invariant Natural Killer T cells (iNKT) are CD1d-restricted T cells characterized by the expression of an invariant TCR alpha-chain (Vα24-Jα18) and markers of NK cells. They are potent cytokine producers, have immunoregulatory potential and can be divided into functionally distinct subsets on the basis of the expression of CD4 and CD8. They are implicated in the induction of T cell tolerance, in the prevention of autoimmune diseases, and in antimicrobial and antitumor immunity [14]. Reduced numbers of iNKT or anergy of iNKT cells have been described in MS patients [5,6,7], with a significant increase following a treatment with beta-interferon, suggesting a protective role of iNKT cells in MS [15]

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