Increased Percentage of CD8CD28 Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis.

Background And Objectives: Fingolimod, an oral therapy for MS, decreases expression of membrane S1P1 receptors on CD4 memory cells, causing their retention and deactivation in lymph nodes. We determined fingolimod effects on the number and proportion of potentially CNS-damaging CD8CD28 cytolytic T lymphocyte cells (CTLs) and on MS-depleted and dysfunctional CD8CD28 anti-inflammatory suppressor/regulatory T cells (Treg) and on CD8 T-cell expression of the CD69 activation/lymph node retention protein in MS.

Methods: CD8, CD28, CD4, and CD69 expression on peripheral blood mononuclear cells was measured with flow cytometry. In vitro concanavalin A (ConA) activation of T cells, including CD8CD28 cells, was used to mimic inflammation.

Results: Fifty-nine patients with MS, 35 therapy-naive (16 clinically stable; 19 exacerbating) and 24 fingolimod-treated (19 clinically stable; 5 exacerbating), and 26 matched healthy controls (HCs) were compared. In therapy-naive patients, the CD8 Treg percent of total lymphocytes was only 1/4 of HC levels. In fingolimod-treated patients, however, CD8 Treg percentages rose to 2.5-fold higher than in HC and 10-fold higher than in therapy-naive MS. With fingolimod therapy, in contrast, CD8 CTL levels were less than half of levels in HCs and therapy-naive patients. In HCs and all MS, activation with ConA strongly induced CD69 expression on CD4 cells and induced 3-fold higher CD69 levels on CD8 CTL than on CD8 Treg. Fingolimod and analogs in vitro did not modify lymphocyte CD69 expression. Lower levels of CD69 on CD8 Treg than on CTL may allow easier Treg egress from lymph nodes and enhance control of peripheral inflammation. In vitro activation reduced the already low CD8 Treg population in therapy-naive MS, but only slightly altered Treg levels in fingolimod-treated MS.

Discussion: Fingolimod therapy markedly increases the percentage of CD8 Treg in MS, reversing the low CD8 Treg:CTL ratio seen in untreated MS. The increase in immune regulatory cells has potential therapeutic benefit in MS. Activation in vitro depletes CD8CD28CTL in patients with MS; the loss is more pronounced in older patients with MS. This suggests that inflammation can disrupt the tenuous immune regulation in MS, especially in older patients.