title: Therapeutic induction of regulatory, cytotoxic CD8+ T cells in multiple sclerosis.
abstract: In the setting of autoimmunity, one of the goals of successful therapeutic immune modulation is the induction of peripheral tolerance, a large part of which is mediated by regulatory/suppressor T cells. In this report, we demonstrate a novel immunomodulatory mechanism by an FDA-approved, exogenous peptide-based therapy that incites an HLA class I-restricted, cytotoxic suppressor CD8+ T cell response. We have shown previously that treatment of multiple sclerosis (MS) with glatiramer acetate (GA; Copaxone) induces differential up-regulation of GA-reactive CD8+ T cell responses. We now show that these GA-induced CD8+ T cells are regulatory/suppressor in nature. Untreated patients show overall deficit in CD8+ T cell-mediated suppression, compared with healthy subjects. GA therapy significantly enhances this suppressive ability, which is mediated by cell contact-dependent mechanisms. CD8+ T cells from GA-treated patients and healthy subjects, but not those from untreated patients with MS, exhibit potent, HLA class I-restricted, GA-specific cytotoxicity. We further show that these GA-induced cytotoxic CD8+ T cells can directly kill CD4+ T cells in a GA-specific manner. Killing is enhanced by preactivation of target CD4+ T cells and may depend on presentation of GA through HLA-E. Thus, we demonstrate that GA therapy induces a suppressor/cytotoxic CD8+ T cell response, which is capable of modulating in vivo immune responses during ongoing therapy. These studies not only explain several prior observations relating to the mechanism of this drug but also provide important insights into the natural immune interplay underlying this human immune-mediated disease.
authors.affiliation: Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Deepani K
authors.initials: DK
authors.lastname: Tennakoon
authors.forename: Riyaz S
authors.initials: RS
authors.lastname: Mehta
authors.forename: Sterling B
authors.initials: SB
authors.lastname: Ortega
authors.forename: Vijay
authors.initials: V
authors.lastname: Bhoj
authors.forename: Michael K
authors.initials: MK
authors.lastname: Racke
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Karandikar
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects* / Q000276:immunology; D005260:Female; D000068717:Glatiramer Acetate; D006680:HLA Antigens / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000502:physiology; D006801:Humans; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D009186:Myelin Sheath / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000097625:HLA-E Antigens
chemical_list: D000068717:Glatiramer Acetate; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D000097625:HLA-E Antigens