Journal article
Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells
Clinical immunology (Orlando, Fla.), Vol.152(1-2), pp.115-126
05/2014
DOI: 10.1016/j.clim.2014.03.005
PMCID: PMC4024444
PMID: 24657764
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.
•Neuroantigen-specific CD8+ T cells are terminally differentiated.•Neuroantigen-specific CD8 suppression is IFNγ, perforin and granzyme B-dependent.•Acute relapse in MS is associated with loss of terminally differentiated CD8+ T cells.•Suppressive potential of neuroantigen-specific CD8 cells can be restored with IL-12.
Details
- Title: Subtitle
- Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells
- Creators
- Khrishen Cunnusamy - Department of Pathology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USAEthan J Baughman - Department of Pathology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USAJorge Franco - Department of Pathology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USASterling B Ortega - Department of Pathology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USASushmita Sinha - Department of Pathology, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USAParul Chaudhary - Department of Neurology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USABenjamin M Greenberg - Department of Neurology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USAElliot M Frohman - Department of Neurology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9072, USANitin J Karandikar - Department of Pathology, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Clinical immunology (Orlando, Fla.), Vol.152(1-2), pp.115-126
- DOI
- 10.1016/j.clim.2014.03.005
- PMID
- 24657764
- PMCID
- PMC4024444
- NLM abbreviation
- Clin Immunol
- ISSN
- 1521-6616
- eISSN
- 1521-7035
- Publisher
- Elsevier Inc
- Grant note
- NIH (http://dx.doi.org/10.13039/100000002) National MS Society
- Language
- English
- Date published
- 05/2014
- Academic Unit
- Pathology
- Record Identifier
- 9984065480502771
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