CD8 T cell responses to myelin oligodendrocyte glycoprotein-derived peptides in humanized HLA-A* 0201-transgenic mice

LT Mars, J Bauer, DA Gross, F Bucciarelli… - The Journal of …, 2007 - journals.aai.org
LT Mars, J Bauer, DA Gross, F Bucciarelli, H Firat, D Hudrisier, F Lemonnier…
The Journal of Immunology, 2007journals.aai.org
Multiple sclerosis (MS) is a demyelinating inflammatory disease of the CNS. Though
originally believed to be CD4-mediated, additional immune effector mechanisms, including
myelin-specific CD8+ T cells, are now proposed to participate in the pathophysiology of MS.
To study the immunologic and encephalitogenic behavior of HLA-A* 0201-binding myelin-
derived epitopes in vivo, we used a humanized HLA-A* 0201-transgenic mouse model.
Eight HLA-A* 0201-binding peptides derived from myelin oligodendrocyte glycoprotein …
Abstract
Multiple sclerosis (MS) is a demyelinating inflammatory disease of the CNS. Though originally believed to be CD4-mediated, additional immune effector mechanisms, including myelin-specific CD8+ T cells, are now proposed to participate in the pathophysiology of MS. To study the immunologic and encephalitogenic behavior of HLA-A* 0201-binding myelin-derived epitopes in vivo, we used a humanized HLA-A* 0201-transgenic mouse model. Eight HLA-A* 0201-binding peptides derived from myelin oligodendrocyte glycoprotein (MOG), an immunodominant myelin self-Ag, were identified in silico. After establishing their relative affinity for HLA-A* 0201 and their capacity to form stable complexes with HLA-A* 0201 in vitro, their immunological characteristics were studied in HLA-A* 0201-transgenic mice. Five MOG peptides, which bound stably to HLA-A* 0201 exhibited strong immunogenicity by inducing a sizeable MOG-specific HLA-A* 0201-restricted CD8+ T cell response in vivo. Of these five candidate epitopes, four were processed by MOG-transfected RMA target cells and two peptides proved immunodominant in vivo in response to a plasmid-encoding native full-length MOG. One of the immunodominant MOG peptides (MOG 181) generated a cytotoxic CD8+ T cell response able to aggravate CD4+-mediated EAE. Therefore, this detailed in vivo characterization provides a hierarchy of candidate epitopes for MOG-specific CD8+ T cell responses in HLA-A* 0201 MS patients identifying the encephalitogenic MOG 181 epitope as a primary candidate.
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