Differential recognition of MBP epitopes in BALB/c mice determines the site of inflammatory disease induction.
Although myelin basic protein (MBP)-recognizing T cells are not readily obtained after immunization of BALB/c mice with MBP (reflecting the BALB/c resistance to actively induced experimental autoimmune encephalomyelitis (EAE)), they can be expanded and cloned after several rounds of in vitro culture. The majority of BALB/c-derived clones recognize an epitope defined by MBP peptide 59-76. When transferred to naive BALB/c recipients, these clones cause classical EAE, with characteristic inflammation and demyelination of the central nervous system (CNS). We previously showed that two related clones recognizing a minor epitope, defined by MBP peptide 151-168, cause inflammation and demyelination preferentially of the peripheral nervous system (PNS). Because MBP has alternatively spliced isoforms, residues 151-168 are not present contiguously in all MBP isoforms. In order to determine whether induction of PNS disease is idiosyncratic to these sister clones, or related to their properties of epitope recognition, an independent T-cell line with similar recognition properties was studied. Clone 116F, derived from a BALB/c shiverer mouse, expresses a different T-cell receptor (TCR), with distinct TCR contact residues, but like the previously described T cells, this clone requires residues from both exons 6 and 7 for optimal stimulation. When adoptively transferred to BALB/c recipients, this clone preferentially induces disease of the PNS. A control BALB/c shiverer-derived MBP 59-76-recognizing clone, in contrast, induces CNS disease. These data strongly suggest that the site of disease initiation may correlate with epitope recognition, particularly when alternative isoforms are involved.
Yoshizawa
I
I
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Bronson
R
R
Ben-Nun
A
A
Richert
J R
JR
Dorf
M E
ME
Abromson-Leeman
S
S
D017398:Alternative Splicing / Q000276:immunology; D019943:Amino Acid Substitution; D000818:Animals; D000918:Antibody Specificity; D002999:Clone Cells; D003001:Cloning, Molecular; D003711:Demyelinating Diseases / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D005091:Exons / Q000235:genetics / Q000276:immunology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008818:Mice, Neurologic Mutants; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology*; D009443:Neuritis / Q000276:immunology*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D017933:Peripheral Nervous System / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000032:analysis / Q000276:immunology; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology
D000939:Epitopes; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell