Unique Clinical and Pathological Features in HLA-DRB1*0401–restricted MBP 111–129–specific Humanized TCR Transgenic Mice

Abstract

Amino acid residues 111–129 represent an immunodominant epitope of myelin basic protein (MBP) in humans with human leukocyte antigen (HLA)-DRB1*0401 allele(s). The MBP 111–129–specific T cell clone MS2-3C8 was repeatedly isolated from a patient with multiple sclerosis (MS), suggesting an involvement of MS2-3C8 T cells in the pathogenesis. To address the pathogenic potential of the MS2-3C8 T cell clone, we generated transgenic (Tg) mice expressing its T cell receptor and restriction element, HLA-DRB1*0401, to examine the pathogenic characteristics of MS2-3C8 Tg T cells by adoptive transfer into HLA-DRB1*0401 Tg mice. In addition to the ascending paralysis typical of experimental autoimmune encephalomyelitis, mice displayed dysphagia due to restriction in jaw and tongue movements and abnormal gait. In accordance with the clinical phenotype, infiltrates of MS2-3C8 Tg T cells and inflammatory lesions were predominantly located in the brainstem and the cranial nerve roots in addition to the spinal cord and spinal nerve roots. Together, these data suggest a pathogenic role of MBP-specific T cells in inflammatory demyelination within the brainstem and cranial nerve roots during the progression of MS. This notion may help to explain the clinical and pathological heterogeneity of MS.

Different Development of Myelin Basic Protein Agonist- and Antagonist-Specific Human TCR Transgenic T Cells in the Thymus and Periphery

“…Therefore, we next examined thymic and peripheral development of MS2-3C8 TCR Tg T cells. In accordance with our previous report (12), development of MS2-3C8 TCR Tg CD4 ϩ T cells was reduced in the thymus of MS2-3C8 TCR Tg/RAG1 KO mice, although the cells were positively selected in the MS2-3C8 TCR Tg/RAG1 wild-type mice (Fig. 6).…”

“…HLA-DRB1*0401, HLA-DRB1*0404, MS2-3C8 TCR, and HD4-1C2 TCR Tg mice were generated in our laboratory previously (6,12,20) and maintained in our animal facility. These mice were housed in specific pathogen-free facilities.…”

“…Because myelin basic protein (MBP)-reactive T cells have been suggested to be involved in the development of MS and MBP residues 111-129 constitute an immunodominant epitope of MBP in humans expressing the HLA-DRB1*0401 haplotype, Tg mice expressing the HLA-DRB1*0401-restricted MBP 111-129 -specific human TCR gene (see Fig. 1A) were created (12). The MBP 111-129 epitope sequence is different between humans and mice [human MBP122: Arg (122R) and murine MBP122:Lys (122K)].…”

“…The HD4-1C2 TCC proliferated in response only to human MBP 111-129 , whereas the MS2-3C8 TCC proliferated in response to both human and mouse MBP [111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129] . Due to the cross-reactivity of MS2-3C8 TCR with mouse MBP 111-129 , the MS2-3C8 TCR Tg T cells can induce experimental autoimmune encephalomyelitis in HLA-DRB1*0401 Tg mice, whereas HD4-1C2 TCR Tg T cells cannot (12).…”

Identification of the Docking Site for CD3 on the T Cell Receptor β Chain by Solution NMR

“…The pathogenic potential of MS2-3C8 was demonstrated using mice transgenic for this TCR and HLA-DR4 (31). An x-ray crystal structure of TCR MS2-3C8 bound to its pMHC ligand, MBP-HLA-DR4, has been determined (30), as well as that of the ternary complex formed by MS2-3C8, MBP-HLA-DR4, and CD4 (32).…”