Programmed death 1 is highly expressed on CD8⁺CD57⁺ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein–Barr virus

Abstract

Summary Growing evidence points to a deregulated response to Epstein–Barr virus (EBV) in the central nervous system of patients with multiple sclerosis (MS) as a possible cause of disease. We have investigated the response of a subpopulation of effector CD8+ T cells to EBV in 36 healthy donors and in 35 patients with MS in active and inactive disease. We have measured the expression of markers of degranulation, the release of cytokines, cytotoxicity and the regulation of effector functions by inhibitory receptors, such as programmed death 1 (PD‐1) and human inhibitor receptor immunoglobulin‐like transcript 2 (ILT2). We demonstrate that polyfunctional cytotoxic CD8+ CD57+ T cells are able to kill EBV‐infected cells in healthy donors. In contrast, an anergic exhaustion‐like phenotype of CD8+ CD57+ T cells with high expression of PD‐1 was observed in inactive patients with MS compared with active patients with MS or healthy donors. Detection of CD8+ CD57+ T cells in meningeal inflammatory infiltrates from post‐mortem MS tissue confirmed the association of this cell phenotype with the disease pathological process. The overall results suggest that ineffective immune control of EBV in patietns with MS during remission may be one factor preceding and enabling the reactivation of the virus in the central nervous system and may cause exacerbation of the disease.

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

“…MS does not develop in the absence of exposure to EBV, and EBV is a 'required', but insufficient on its own, contributor in early disease pathophysiology. Independent support comes from an observed higher rate of EBV activation in MS [22,23], a role for EBV in triggering new relapses consistent with a reduced ability of EBV-specific CD8 + T cells (e.g., T cell exhaustion, see Glossary) to limit EBV reactivation in MS patients [24,25], and a strong correlation between the presence of anti-EBV antibodies in blood and disease onset [26][27][28][29]. Evidence of CNS involvement comes from reports of elevated anti-EBNA1 IgG serology associated with the appearance of new gadolinium (Gd)enhancing brain lesions [30] and the presence, in patients, of EBNA1-specific T cells recognizing myelin [31].…”

Regenerating Immunotolerance in Multiple Sclerosis with Autologous Hematopoietic Stem Cell Transplant

“…A study in type 1 diabetes mellitus demonstrated an early rise in T effector cells in the “short-response” population, opposed to the delayed rise in T central memory populations noted in the “prolonged-response” cohort ( 152 ). Recent work in MS has demonstrated that the inflammatory response of CD8 + CD57 + cells correlates with relapse frequency, thereby confirming the relevance of this population to disease activity ( 153 ).…”

Challenges and Opportunities for Biomarkers of Clinical Response to AHSCT in Autoimmunity

“…CD27 − CD45RO − long-term memory CD8 T cells transiently diminished and reached pretherapy proportions at 36 months post-AHSCT (Figure 2 H). A relative expansion of potentially senescent ( 5 ) CD28 − CD56 − CD57 + CD8 T cells (Figure 2 I) was observed after AHSCT at the expense of cytotoxic CD28 − CD56 + CD57 + CD8 T cells (Figure 2 J). These results are consistent with previous immunophenotyping studies in patients with MS and other autoimmune diseases treated with AHSCT ( 6 – 11 ).…”