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

Abstract:

: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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Friese MA,Jakobsen KB,Friis L,Etzensperger R,Craner MJ,McMahon RM,Jensen LT,Huygelen V,Jones EY,Bell JI,Fugger L

doi

10.1038/nm.1881

subject

Has Abstract

pub_date

2008-11-01 00:00:00

pages

1227-35

issue

11

eissn

1078-8956

issn

1546-170X

pii

nm.1881

journal_volume

14

pub_type

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