Transcription Factor c-Maf Promotes Immunoregulation of Programmed Cell Death 1–Expressed CD8 ⁺ T Cells in Multiple Sclerosis

Abstract

Background and ObjectivesMultiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. CD8+ T cells are prominently found at inflammatory sites. Recent advances in understanding checkpoint molecules, including programmed cell death 1 (PD-1), expressed on CD8+ T cells, highlight the immune regulatory roles of this T-cell subset; however, the role of CD8+ T cells in MS is unclear. Thus, we aimed to reveal the characteristics of PD-1–expressed (PD-1+) CD8+ T cells in MS.MethodsWe performed a cohort, case-control study for phenotyping analysis of PD-1+CD8+ T cells in disease remission and flare states using CSF and peripheral blood samples of 45 patients with MS or clinically isolated syndrome and 12 healthy subjects. We further analyzed the transcriptome of sorted PD-1+CD8+ T cells obtained from interferon (IFN)-β–treated patients and validated their regulatory machinery using in vitro cell culture assays with lentiviral gene transfer.ResultsIn the disease remission state, PD-1+CD8+ T cells were decreased in the peripheral blood of patients with MS and resolved in patients treated with IFN-β treatment who showed immune regulatory cytokine interleukin (IL)-10 expression. In the disease flare state, we found that PD-1+CD8+ T cells were enriched in the CSF, which predicted a good response to subsequent IV steroid therapy. Transcriptome analysis of sorted PD-1+CD8+ T cells revealed the transcription factor c-Maf as a potential major regulator of the gene module, including multiple coinhibitory molecules. Furthermore, c-Maf expressed in CD8+ T cells induced PD-1 expression and production of IL-10 as well as suppressed alloactivated CD4+ T-cell survival.DiscussionThis study uncovered a favorable role of PD-1+CD8+ T cells against MS and demonstrated that c-Maf–driven IL-10 is an immune regulatory machinery.

Programmed Cell Death Protein 1–Positive CD8 + T Cells in Multiple Sclerosis

“… 15 Alternatively, high IL-10 expression is a hallmark of exhausted CD8 + T cells. However, exhausted CD8 + T cells also show low expression of proinflammatory cytokines and lytic mediators, which was not found by Koto et al 6 The increased expression of inhibitory receptors (also CTLA-4 and TIGIT) is consistent with an exhausted phenotype, as is the high expression of the transcription factor c-Maf. c-Maf has been identified as key regulator of CD8 + T-cell exhaustion in the context of melanoma-derived T cells.…”

“… 8 The lower abundance of PD-1 + cells could reflect a distinct distribution and/or defective formation of memory T cells, as has been hypothesized to underlie the defective control of Epstein-Barr virus (EBV) by CD8 + T cells in MS. 8 Vice versa, a higher expression of PD-1 by CD8 + CD57 + T cells has been described as phenotypic characteristic of CD8 + T cells defective in the control of EBV in stable MS. 9 Because IFN-β suppresses VLA-4 expression on lymphocytes, 10 PD-1 + CD8 + T cells could migrate toward the CNS and therefore be reduced in the circulation. Indeed, CD8 + PD-1 + T cells make up a major part of T cells observed in MS lesions 11 as well as in clusters of CSF CD8 + T cells associated with (premorbid) MS. 12 Accordingly, Koto et al 6 show a higher expression of PD-1 on CSF CD8 + T cells in MS compared with PBMC.…”

“…In this issue of Neurology® Neuroimmunology & Neuroinflammation , Koto et al 6 investigated the association of CD8 + T cells positive for PD-1 with the disease course of MS and provide a further transcriptional characterization of these cells. They show a reduced presence of PD-1 + CD8 + T cells in the circulation of people with MS, which was recovered by interferon beta (IFN-β) therapy.…”

“…The high expression of PD-1 on CSF CD8 + T cells could reflect cellular activation because these cells are also CD69 + . 13 Koto et al 6 show that circulating PD-1 + T cells in IFN-β–treated individuals highly expressed IL-10, whereas expression of proinflammatory cytokines or lytic mediators was not distinct from circulating PD-1 − cells. In CD4 + T cells and B cells, IL-10 expression has been mostly associated with anti-inflammation, which could be beneficial for the course of MS. 14 Anti-inflammatory IL-10 + CD8 + T cells have been identified in the experimental autoimmune encephalomyelitis mouse model of neuroinflammation.…”

PD-1/PD-L Axis in Neuroinflammation: New Insights

“…In fact, in the disease remission state, CD8 + PD-1 + T cells were decreased in the peripheral blood of patients with MS and resolved in patients treated with IFN-β treatment who showed immune-regulatory cytokine interleukin (IL)-10 expression. On the other hand, CD8 + PD-1 + T cells were enriched in the CSF of MS patients, which predicted a good response to subsequent IV steroid therapy ( 92 ).…”