title: Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells.
abstract: Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Although its etiology remains unknown, pathogenic T cells are thought to underlie MS immune pathology. We recently showed that MS patients harbor CNS-specific CD8+ Tregs that are deficient during disease relapse. We now demonstrate that CNS-specific CD8+ Tregs were cytolytic and could eliminate pathogenic CD4+ T cells. These CD8+ Tregs were present primarily in terminally differentiated (CD27-, CD45RO-) subset and their suppression was IFNγ, perforin and granzyme B-dependent. Interestingly, MS patients with acute relapse displayed a significant loss in terminally differentiated CD8+ T cells, with a concurrent loss in expression of perforin and granzyme B. Pre-treatment of exacerbation-derived CD8+ T cells with IL-12 significantly restored suppressive capability of these cells through upregulation of granzyme B. Our studies uncover immune-suppressive mechanisms of CNS-specific CD8+ Tregs, and may contribute to design of novel immune therapies for MS.
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USA.
authors.forename: Khrishen
authors.initials: K
authors.lastname: Cunnusamy
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USA.
authors.forename: Ethan J
authors.initials: EJ
authors.lastname: Baughman
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Franco
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USA.
authors.forename: Sterling B
authors.initials: SB
authors.lastname: Ortega
authors.affiliation: Department of Pathology, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USA.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Department of Neurology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USA.
authors.forename: Parul
authors.initials: P
authors.lastname: Chaudhary
authors.affiliation: Department of Neurology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Greenberg
authors.affiliation: Department of Neurology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USA.
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Frohman
authors.affiliation: Department of Pathology, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USA. Electronic address: nitin-karandikar@uiowa.edu.
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Karandikar
mesh_terms: D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D018450:Disease Progression; D005260:Female; D053804:Granzymes / Q000096:biosynthesis / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D054353:Perforin / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D015395:Histocompatibility Antigens Class I; D053645:Interleukin-2 Receptor alpha Subunit; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D054353:Perforin; D018664:Interleukin-12; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; D053804:Granzymes
keywords: CD8; IL-12; Multiple sclerosis; Regulatory; T cells