Distinct Properties of Circulating CD8+ T Cells in FTY720-Treated Patients With Multiple Sclerosis

Objective: To define the capacity of peripheral blood CD8(+) T cells from patients with multiple sclerosis (MS) receiving fingolimod (FTY720) to migrate in response to chemokines that contribute to trafficking into the central nervous system. Design: Peripheral blood T cells of FTY720-treated patients with MS (MS-FTY) are mainly CD8(+) CCR7(-) effector memory cells as CCR7(+) T cells are inhibited from exiting from secondary lymph nodes. Migration of CD8(+) T cells from MS-FTY patients and untreated donors to chemokines CXCL12 and CCL2 was assayed in vitro. Expression of CCL2 receptor (CCR2), CCR7, CD28, and CD27 on CD8(+) T cells was determined by flow cytometry. Setting: Montreal Neurological Institute's clinical research unit. Patients: The MS-FTY patients were part of the extension phase of FTY720 clinical trials for relapsing-remitting MS. Results: In vitro addition of active (phosphorylated) FTY720 increased migration of CD8(+) T cells from untreated patients to CXCL12 and CCL2. The CD8(+) or CD8(+) CCR7(-) T cells from MS-FTY patients migrated less to CXCL12 and CCL2 compared with those from untreated donors. The proportion of CD8(+) CCR7(-) cells that express the CCL2 chemokine receptor, CCR2, was significantly reduced in the MS-FTY group. The CD8(+) CCR7(-) cells from the MS-FTY patients were enriched with CD27(-) CD28(-) (late effector) memory cells, a population with reduced expression of CCR2 compared with early (CD27(+) CD28(+)) effector memory cells. Conclusions: Therapy with FTY720 results in a subset of CD8(+) T cells with distinct functional migratory properties dominating the peripheral circulation. The expected forthcoming use of FTY720 as a sustained therapy for MS will clarify how this redistribution of lymphocyte populations affects the overall process of immune surveillance.