Fulminant spontaneous autoimmunity of the central nervous system in mice transgenic for the myelin proteolipid protein-specific T cell receptor

Abstract

Proteolipid protein (PLP)-139 -151 is the dominant encephalitogenic peptide that induces experimental autoimmune encephalomyelitis (EAE) in SJL (H-2 s ) mice. To examine the contribution of T cell receptor (TCR) specificity in the induction of EAE, we generated transgenic mice expressing the rearranged TCR genes from an encephalitogenic or a nonencephalitogenic PLP-139 -151͞I-A s -specific T cell clone. Both types of transgenic lines developed spontaneous EAE, but, remarkably, the lines expressing the TCR from the nonencephalitogenic clone showed increasingly higher frequencies of disease (60 -83%) in progressive SJL backcrosses and could not be propagated on the susceptible background. The T cells from the transgenic mice were not tolerized, because they responded vigorously to the antigen in vitro and mediated EAE when the mice were immunized with antigen. Besides being the only description of a TCR transgenic mice for the PLP-139 -151͞I-A s epitope, the results demonstrate that the TCR from a nonencephalitogenic PLP-specific T cell clone can induce autoimmune disease when expressed appropriately in vivo. Myelin proteolipid protein (PLP) is the major protein of the central nervous system (CNS) myelin. Multiple epitopes of PLP that can induce experimental autoimmune encephalomyelitis (EAE) in several different strains of mice have been identified (1-5). In SJL (H-2 s ) mice, there are two major encephalitogenic epitopes of PLP, 6), each of which binds with a binding affinity of K 50 Ͻ 1 M to I-A s (5), but the immune response to PLP-139-151 is unusually dominant. First, immunization of SJL mice with whole spinal cord homogenate that contains multiple myelin antigens including myelin basic protein (MBP), PLP, and myelin oligodendrocyte glycoprotein results in a T cell response directed entirely to the PLP-139-151 epitope (7). Second, if PLP-139-151-specific T cells are tolerized in SJL mice, disease induction by whole spinal cord homogenate is abrogated (8). In addition to the unique features of this epitope, different H-2 s strains show differences in their susceptibility to EAE. Whereas SJL mice are highly susceptible, B10.S mice are relatively resistant to the development of EAE when they are immunized with PLP-139-151. Thus, these mouse strains provide an opportunity to identify the genetic loci and genes that are responsible for disease susceptibility (9).In this paper, we describe the generation of PLP-139-151-specific TCR-transgenic mice by expressing rearranged TCR ␣ and ␤ chains from an encephalitogenic and a nonencephalitogenic T cell clone derived from SJL mice and that are specific for PLP-139-151. The transgenic mice expressing either the encephalitogenic or the nonencephalitogenic TCR developed spontaneous EAE in specific pathogen-free͞viral antibody-free conditions (SPF͞VAF). More importantly, the two lines of transgenic mice expressing TCR from the nonencephalitogenic clone developed spontaneous EAE with such a high frequency that they could not be maintained on the SJL background. Materials and ...

Transgenic models of autoimmune disease

“…One caveat to these experiments is that the behaviour of the TCR transgene does not always reiterate faithfully its history in the T cell clones from which it was derived. One of the most aggressive spontaneous disease phenotypes so far observed in a TCR transgenic model uses a receptor derived from a clone that was originally nonpathogenic [18].…”

Gemfibrozil, a Lipid-lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-activated Receptor-β

“…These Tg mice develop EAE spontaneously in all backcross generations at an overall average occurrence of 40%. However, upon immunization with a low dose of PLP139 -151, these Tg mice exhibit severe EAE (27). Therefore, these Tg mice were immunized subcutaneously with 10 g of PLP139 -151 and 60 g of M. tuberculosis in incomplete Freund's adjuvant.…”

PSGL‐1 and E/P‐selectins are essential for T‐cell rolling in inflamed CNS microvessels but dispensable for initiation of EAE

“…In order to identify the role of lymphocytic PSGL-1 in mediating the rolling and capture of auto-Ag-specific T cells in inflamed spinal cord microvessels during EAE in vivo, we established four WT and two PSGL-1 −/− PLP-specific T-cell lines from PLP-specific TCR tg SJL/J mice [15] and PSGL-1 −/− PLP TCRtg SJL/J mice, respectively. We specifically chose this approach to focus our analysis on the impact of the presence or absence of PSGL-1 on the interaction of autoaggressive T-cells with the inflamed BBB during EAE.…”

“…WT SJL/J T-cell lines were established from the spleen and inguinal lymph nodes of naive PLP-specific TCR-tg SJL/J mice (SJL/J TgN(PLP 5B6 TCR 1858)) [15]. By mating PSGL-1 −/− SJL/J mice and PLP aa139-151 -specific TCR-tg SJL/J mice, we produced PSGL-1 −/− PLP TCRtg SJL/J mice, which allowed for the establishment of PLP-specific T-cell lines accordingly.…”