Two discreet subsets of CD8 T cells modulate PLP 91-110 induced experimental autoimmune encephalomyelitis in HLA-DR3 transgenic mice

Ashutosh K. Mangalam, David Luckey, Shailendra Giri, Michele Smart, Larry R. Pease, Moses Rodriguez, Chella S. David

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Previously we showed that transgenic mice expressing human HLA-DR3 gene are susceptible to PLP 91-110 induced experimental autoimmune encephalomyelitis (EAE) and can serve as an animal model of multiple sclerosis (MS). HLA-DR3 mice with EAE showed increased number of CD8 T cells indicating their important role in disease pathogenesis. The role of CD8 T cells in MS, an inflammatory demyelinating disease of CNS, has been enigmatic as it has been assigned both regulatory and pathogenic roles. Therefore, to evaluate the role of CD8 T cells, we generated CD8 deficient HLA-DR3 transgenic mice (DR3.CD8 -/-). Immunization with PLP 91-110 led to more severe EAE in DR3.CD8 -/- mice compared to HLA-DR3 mice indicating a regulatory role for CD8 T cells. Interestingly, DR3.CD8 -/- mice with EAE showed decreased CNS pathology compared to DR3 mice thus suggesting a pathogenic role for CD8 T cells. We show that these two subsets of CD8 T cells can be differentiated based on the surface expression of CD122 (IL-2 Rβ chain). CD8 T cells expressing CD122 (CD8+CD122+) play a regulatory role while CD8+CD122- T cells act as a pathogenic subset. CD122 expressing CD8 T cells are the regulatory subset of CD8 T cells and regulate the encephalitogenic CD4 T cells through direct modulation of antigen presenting cells and/or through the release of immunoregulatory cytokines such as IL-10, IFNγ and TGFβ. We also showed that adoptive transfer of CD8CD122- T cells caused increased spinal cord demyelination indicating that these are pathogenic subset of CD8 T cells. Our study suggests that CD8+ T cells play both regulatory as well as pathogenic role in disease pathogenesis of EAE. A better understanding of these subsets could aid in designing novel therapy for MS patients.

Original languageEnglish (US)
Pages (from-to)344-353
Number of pages10
JournalJournal of Autoimmunity
Volume38
Issue number4
DOIs
StatePublished - Jun 1 2012

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Keywords

  • CD8 regulatory T cells
  • Cytokine
  • Demyelination
  • Experimental autoimmune encephalomyelitis
  • HLA class II transgenic mice
  • Multiple sclerosis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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