Fingolimod does not impair T-cell release from the thymus and beneficially affects Treg function in patients with multiple sclerosis

Abstract

In multiple sclerosis (MS), disturbed T-cell homeostasis affects both conventional CD4⁺ T cells (Tcon) and regulatory T cells (Treg). Functionally, this is linked to a loss of Treg-suppressive properties. Concerns exist as to whether fingolimod might further aggravate Treg dysfunction by inhibiting thymic egress and, thus, promoting premature immunosenescence. The objective of this paper is to investigate whether fingolimod, by sequestration of developing cells in the thymus, might deteriorate numeric and/or functional disequilibrium of T-cell subtypes. We assessed numbers and phenotypes of blood Tcon and Treg in 74 MS patients treated with fingolimod and in 37 healthy donors. Treg and Tcon were also analyzed for immunoreactivity, suppressive function, sphingosine-1-phosphate-triggered (S1P) trafficking, and S1P-receptor expression. This was complemented by assessing surrogate markers of thymic T-cell development, including frequencies of cells expressing T-cell receptors (TCR) of dual specificity, and TCR diversity in Treg. Fingolimod did not negatively affect naive T-cell phenotypes or markers of thymic T-cell development. By reducing CCR7-expressing Tcon, fingolimod increased relative proportions of Treg. As a result of this shift, fewer proliferative CCR7⁻ Tcon became enriched and Treg-dysfunction was indirectly reversed. These observations argue against harmful interference of fingolimod with thymic T-cell output that, particularly in pediatric MS, might possibly counteract its beneficial effects.