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Expansion of CD4⁺CD28^- T cells producing high levels of interferon- in peripheral blood of patients with multiple sclerosis

¹ Division of Immunobiology, Research Section of Pathophysiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
² Division of Immunobiology, Research Section of Pathophysiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
³ Department of Neurology, Sapporo Minami National Hospital, Sapporo, Japan
⁴ Sapporo Neurology Clinic, Sapporo, Japan
⁵ Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

^* To whom correspondence should be addressed.

	Abstract

CD4⁺ T cells that lack surface expression of the CD28 co-stimulatory molecule (CD4⁺CD28^- T cells) were expanded in peripheral blood of patients with multiple sclerosis (MS) [5.20 ± 1.67% vs 13.00 ± 2.68% (healthy controls (HC) versus patients with MS)]. Both the CD4⁺CD28⁺ and CD4⁺CD28^- T-cell populations of patients with MS produced higher levels of interferon (IFN)- compared with those in HC. In particular, the proportion of IFN-⁺ cells among CD4⁺CD28^- T cells from patients with MS was considerably high. However, expression of co-stimulatory molecules including inducible costimulator (ICOS), activating natural killer receptors, or members of tumor necrosis factor receptor family that replace CD28 in CD4⁺CD28^- T cells of patients with MS could not be identified. A unique subpopulation bearing the CD45RA^highCCR7^- phenotype was identified among the CD4⁺CD28^- T cells of some patients with MS. Because only MS samples contained this CD45RA^highCCR7^- population attributed to terminally differentiated effector memory cells and lacked naive CD45RA^highCCR7⁺ cells, we suggest that CD4⁺CD28^- T cells of patients with MS represent a cell population which is in more differentiated state than healthy subjects. In patients treated with IFN--1b, IFN- production from CD4⁺CD28⁺ T cells was suppressed compared with that in untreated patients. On the contrary, in the CD4⁺CD28^- population, production of IFN- in IFN--1b-treated patients was not significantly suppressed compared with that in untreated patients with MS. Thus, an additional treatment strategy that specifically targets this cell population may enhance the beneficial effect of IFN- on MS.

Key Words: CD4⁺CD28^- T cells, co-stimulation, interferon-, interferon-, interleukin-17, multiple sclerosis

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