The myelin basic protein-specific T cell repertoire in (transgenic) Lewis rat/SCID mouse chimeras: preferential V beta 8.2 T cell receptor usage depends on an intact Lewis thymic microenvironment.
In the Lewis rat, myelin basic protein (MBP)-specific, encephalitogenic T cells preferentially recognize sequence 68-88, and use the V beta 8.2 gene to encode their T cell receptors. To analyze the structural prerequisites for the development of the MBP-specific T cell repertoire, we reconstituted severe-combined immunodeficient (SCID) mice with fetal (embryonic day 15-16) Lewis rat lymphoid tissue, and then isolated MBP-specific T cell lines from the adult chimeras after immunization. Two types of chimera were constructed: SCID mice reconstituted with rat fetal liver cells only, allowing T cell maturation within a chimeric SCID thymus consisting of mouse thymic epithelium and rat interdigitating dendritic cells, and SCID mice reconstituted with rat fetal liver cells and rat fetal thymus grafts, allowing T cell maturation within the chimeric SCID and the intact Lewis rat thymic microenvironment. Without exception, the T cell lines isolated from MBP-immunized SCID chimeras were restricted by MHC class II of the Lewis rat (RT1.B1), and none by I-Ad of the SCID mouse. Most of the T cell lines recognized the immunodominant MBP epitope 68-88. In striking contrast to intact Lewis rats, in SCID mice reconstituted by rat fetal liver only, MBP-specific T cell clones used a seemingly random repertoire of V beta genes without a bias for V beta 8.2. In chimeras containing fetal Lewis liver plus fetal thymus grafted under the kidney capsule, however, dominant utilization of V beta 8.2 was restored. The migration of liver-derived stem cells through rat thymus grafts was documented by combining fetal tissues from wild-type and transgenic Lewis rats. The results confirm that the recognition of the immunodominant epitope 68-88 by MBP-specific encephalitogenic T cells is a genetically determined feature of the Lewis rat T cell repertoire. They further suggest that the formation of the repertoire requires T cell differentiation in a syngeneic thymic microenvironment.
Kääb
G
G
Max-Planck-Institute for Psychiatry, Martinsried, Germany.
Brandl
G
G
Marx
A
A
Wekerle
H
H
Bradl
M
M
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D016332:Fetal Tissue Transplantation; D016031:Liver Transplantation; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology*; D011828:Radiation Chimera; D051381:Rats; D011917:Rats, Inbred Lew; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D012641:Selection, Genetic; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000637:transplantation*
D004676:Myelin Basic Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta