Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis.
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Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis. / Friese, Manuel A.; Jakobsen, Karen B; Friis, Lone; Etzensperger, Ruth; Craner, Matthew J; McMahon, Róisín M; Jensen, Lise T; Huygelen, Véronique; Jones, E Yvonne; Bell, John I; Fugger, Lars.
In: NAT MED, Vol. 14, No. 11, 11, 2008, p. 1227-1235.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis.
AU - Friese, Manuel A.
AU - Jakobsen, Karen B
AU - Friis, Lone
AU - Etzensperger, Ruth
AU - Craner, Matthew J
AU - McMahon, Róisín M
AU - Jensen, Lise T
AU - Huygelen, Véronique
AU - Jones, E Yvonne
AU - Bell, John I
AU - Fugger, Lars
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 14
SP - 1227
EP - 1235
JO - NAT MED
JF - NAT MED
SN - 1078-8956
IS - 11
M1 - 11
ER -
