Lars Henrik Fugger

Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Manuel A Friese, Denmark
  • Karen B Jakobsen, Denmark
  • Lone Friis, Denmark
  • Ruth Etzensperger, Denmark
  • Matthew J Craner, Denmark
  • Róisín M McMahon, Denmark
  • Lise Torp Jensen
  • Véronique Huygelen, Denmark
  • E Yvonne Jones, Denmark
  • John I Bell, Denmark
  • Lars Fugger
The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4(+) T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8(+) T cells are controversial. We have generated humanized mice expressing the multiple sclerosis-associated MHC class I alleles HLA-A(*)0301 (encoding human leukocyte antigen-A3 (HLA-A3)) and HLA-A(*)0201 (encoding HLA-A2) and a myelin-specific autoreactive T cell receptor (TCR) derived from a CD8(+) T cell clone from an individual with multiple sclerosis to study mechanisms of disease susceptibility. We demonstrate roles for HLA-A3-restricted CD8(+) T cells in induction of multiple sclerosis-like disease and for CD4(+) T cells in its progression, and we also define a possible mechanism for HLA-A(*)0201-mediated protection. To our knowledge, these data provide the first direct evidence incriminating MHC class I genes and CD8(+) T cells in the pathogenesis of human multiple sclerosis and reveal a network of MHC interactions that shape the risk of multiple sclerosis.
Original languageEnglish
JournalNature Medicine
Volume14
Issue11
Pages (from-to)1227-35
Number of pages8
ISSN1078-8956
DOIs
Publication statusPublished - 2008

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