THE MYELIN BASIC PROTEIN-SPECIFIC T-CELL REPERTOIRE IN (TRANSGENIC) LEWIS RAT SCID MOUSE CHIMERAS - PREFERENTIAL V-BETA-8.2 T-CELL RECEPTORUSAGE DEPENDS ON AN INTACT LEWIS THYMIC MICROENVIRONMENT

In the Lewis rat, myelin basic protein (MBP)-specific, encephalitogeni c 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 p rerequisites for the development of the MBP-specific T cell repertoire , we reconstituted severe-combined immuno-deficient (SCID) mice with f etal (embryonic day 15-16) Lewis rat lymphoid tissue, and then isolate d MBP-specific T cell lines from the adult chimeras after immunization . Two types of chimera were constructed: SCID mice reconstituted with rat feral liver cells only, allowing T cell maturation within a chimer ic SCID thymus consisting of mouse thymic epithelium and rat interdigi tating dendritic cells, and SCID mice reconstituted with rat fetal liv er cells and rat fetal thymus grafts, allowing T cell maturation withi n the chimeric SCID and the intact Lewis rat thymic microenvironment. Without exception, the T cell lines isolated from MBP-immunized SCID c himeras were restricted by MHC class II of the Lewis rat (RT1.B-1). an d none by I-A(d) of the SCID mouse. Most of the T cell lines recognize d the immunodominant MBP epitope 68-88. In striking contrast to intact Lewis rats, in SCID mice reconstituted by rat fetal liver only MBP-sp ecific T cell clones used a seemingly random repertoire of V beta gene s without a bias for V beta 8.2. In chimeras containing fetal Lewis li ver plus fetal thymus grafted under the kidney capsule, however, domin ant utilization of V beta 8.2 was restored. The migration of liver-der ived stem cells through rat thymus grafts was documented by combining fetal tissues from wild-type and transgenic Lewis rats. The results co nfirm 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 form ation of the repertoire requires T cell differentiation in a syngeneic thymic microenvironment.