ENCEPHALITOGENIC T CELL CLONES SPECIFIC FOR MYELIN BASIC PROTEIN An Unusual Bias in Antigen Recognition (original) (raw)
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Encephalitogenic MHC restricted T cell clones specific for the autoantigen myelin basic protein
Experimental allergic encephalomyelitis (EAE) 1 is a clear example of an autoimmune disease mediated by class II-restricted T lymphocytes (1-5). Certain forms of EAE are characterized by relapsing paralysis, with histopathology revealing both perivascular lymphocytic cuffs and demyelination. Because of these features, chronic relapsing EAE is often cited as a model for the human disease multiple sclerosis (MS) (6). Further similarities exist between EAE and MS, including the presence of T helper cells in the inflammatory lesions (7, 8), and the linkage of susceptibility for both EAE and MS to immune response genes (9, 10). With the capability for cloning antigen-specific T cells (1 1), it is now possible to analyze the precise cellular and immunogenetic mechanisms involved in EAE.
Journal of Neuroimmunology, 1988
The C-terminal 89-169 amino acid fragment of myelin basic protein (MBP) causes experimental allergic encephalomyelitis (EAE) in SJL/J mice. In order to identify the encephalitogenic T cell epitope, we have examined the fine specificity of encephalitogenic SJL/J T cell clones with synthetic peptides derived from the C-terminal 89-169 amino acids of MBP. These peptides were examined for their immunogenic and encephalitogenic activity in the SJL/J mouse. The SJL/J-derived, encephalltogenic T cell clone, 4b.14a, was shown to be responsive to rat myelin basic protein synthetic peptides pR89-101 (VHFFKNIVTPRTP) as well as to intact MBP. Its response was effectively blocked by mAb 10-2.16 (anti-I-A s) as was the response to intact MBP. Furthermore, pR89-101 was revealed to be highly immunogenic for the (PLSJ)F 1 mouse in terms of lymphocyte proliferation, but not for the PL/J mouse, in spite of the fact that there exists a strong bias to H-2 u restricted responses in the (PLSJ)F 1 mouse at the T cell level. By using pR89-101, T cells of (PLSJ)F1 origin were revealed to recognize the peptide in association with the I-A s molecule on (PLSJ)F1 antigen presenting cells (APC). When examined for
Journal of immunology (Baltimore, Md. : 1950), 1995
The cellular immunology of experimental autoimmune encephalomyelitis, a model for multiple sclerosis, has been studied, for the most part, using T cells directed to dominant epitopes of the Ag myelin basic protein (MBP). To characterize T cells reactive to cryptic epitopes of MBP, we immunized Lewis rats with each of 17 overlapping peptides of the 18.5-kDa isoform of rat MBP. We found that, in addition to the known 71-90 epitope, six other peptides induced active encephalomyelitis in the majority the injected rats. T cell lines raised to six different MBP epitopes were encephalitogenic upon adoptive transfer to naive rats. In contrast to the T cells specific for the dominant 71-90 peptide, the T cell lines reactive to cryptic epitopes were not restricted in their TCR genes to V beta 8.2, and some of the lines caused prolonged disease. Thus, T cells of different specificities and TCR usage can be pathogenic.
Proceedings of the National Academy of Sciences, 1988
The peptide p89-101 (Val-His-Phe-Phe-Lys-Asn-lle-Val-Thr-Pro-Arg-Thr-Pro) of myelin basic protein is encephalitogenic in mice expressing H-2q and H-2S antigens. Six of 13 encephalitogen-specific T-cell clones were shown to express the variable a-chain (Va) 17a gene product (KJ23a'), whereas seven clones were KJ23a-. Both KJ23a' and KJ23asubpopulations were encephalitogenic in'SJL/J mice when adoptively transferred. Depletion of KJ23a+ cells in vivo with the administration of the antibody KJ23a suppresses expenmental allergic encephalomyelitis induced with KJ23a+ T-cell lines. However, experimental allergic encephalomyelitis induced with either (i) encephalitogenic peptide p89-101, (u) intact myelin basic protein, or (iii) KJ23a-T cells reactive to p89-101 cannot be prevented with monoclonal antibody KJ23a.
Evaluation of a rat model of experimental autoimmune encephalomyelitis with human MBP as antigen
Cellular & molecular immunology, 2004
Experimental autoimmune encephalomyelitis (EAE) is a good model for human multiple sclerosis (MS) research. However, there are some defects in the traditional models. Here, we improved the model by using the human myelin basic protein (MBP) as antigen. EAE was induced by immunization of female Wistar rats with human MBP. Compared with the traditional models, the new model was evaluated by clinical signs to pathological changes. The immune state of the model was assessed by the lymphocyte infiltrative response and levels of TNF-alpha, IFN-gamma, IL-10. It was found that most of rats exhibited tail tone loss and hind-limb paralysis, also there were demyelination, infiltrative lymphocyte foci, "neuronophagia" in the cortex of cerebra and the white matter of spinal cords. PBMCs and spleen lymphocytes were strongly responsive to the stimulation of MBP and PHA. The levels of TNF-alpha and IFN-gamma were altered with the severity of EAE. In the remitting phase, IL-10 was increase...
The Journal of …, 1987
The role of class II restriction in T cell recognition of an epitope of the autoantigen myelin basic protein (MBP) has been investigated. Encephalitogenic PL/J(H-2u) and (PL/J X SJL/J(H-2s))F1 ((PLSJ)F1) clones, isolated after immunization with intact MBP, recognize the N-terminal 11 amino acid residues of MBP in association with I-Au class II molecules. The synthetic peptide MBP 1-11 has been tested in vivo for induction of EAE. Clinical and histological EAE occurs in PL/J and (PLSJ)F1 mice but not SJL/J. The class II restriction of T cells primed with MBP 1-11 has been examined in primary cultures in vitro. Similar to encephalitogenic T cell clones, isolated after continuous selection in vitro, the population of MBP 1-11-specific proliferative PL/J and (PLSJ)F1 T cells, recognize this epitope in association with I-Au class II molecules. Not all MBP-specific T cell clones which are restricted to I-Au class II molecules cause autoimmune encephalomyelitis. The specificity of these non-encephalitogenic clones has been examined in this report. These clones also recognize MBP 1-11. Thus recognition of an encephalitogenic T cell epitope is not sufficient for induction of EAE.
Journal of Experimental Medicine, 1988
Experimental allergic encephalomyelitis (EAE) is a model for autoimmune disease mediated by antigen-specific, class II-restricted T cells. The autoantigen in EAE is myelin basic protein (MBP), a 17-kD multideterminant protein from CNS myelin (1) . As for other murine T cell-mediated autoimmune diseases, susceptibility to EAR is associated with allelic I-A class II molecules (1-3) . Initial investigations demonstrated that encephalitogenic determinants were located only within the NH2-terminal 1-37 and COOH-terminal 89-169 MBP fragments (1). Encephalitogenic T cell epitopes within these two fragments have been identified. T cell recognition of MBP pl-11 is restricted by I-A°(2), and recognition of MBP p89-101 is restricted by I-As (3) . I-E-restricted antigen-specific T cells that participate in EAE or other murine autoimmune diseases have not been previously identified.
Journal of Experimental Medicine, 1994
An immunodominant epitope of myelin basic protein (MBP), VHFFKNIVTPRTP (p87-99), is a major target of T cells in lesions of multiple sclerosis (MS) and in experimental allergic encephalomyelitis (EAE). T cells found in EAE lesions bear the same amino acids in the third complementary determining region of the T cell receptor (TCK) as those found in MS lesions. We analyzed the trimolecular interactions between MBP p87-99, dass II major histocompatibility complex (MHC), and TCK, and designed soluble inhibitors for therapy. F, N, I, and V at positions 90, 92, 93, and 94 interact with MHC, whereas K, T, and P at positions 91, 95, and 96 interact with TCK. The peptides, p87-99195T>A] and p87-99196P>A] could compete more effectively with p87-99 for binding to MHC and could antagonize the in vitro response ofT cells to p87-99 more effectively than p87-99191K>A]. However, only p87-99191K>A] prevented and reversed EAE, indicating that the extent of MHC or TCK competition does not predict success in treating EAE. To elucidate the mechanism of inhibition of EAE, draining lymph node cells from rats immunized with the native peptide alone or together with each of the three TCR antagonists were challenged in vitro with p87-99. Administration of p87-99191K>A], but not p87-99 [9ST>A] or p87-99196P>A], reduced the production of tumor necrosis factor (TNF)-oe and interferon (IFN) 3'. IFN-3" and TNF-ol are two cytokines that are critical in the pathogenesis of EAE and MS. E xperimental allergic encephalomyelitis (EAE) 1 is a T cellmediated autoimmune disease of the central nervous system (1, 2). The TCK recognizes peptide bound to an MHC molecule (3). Several groups, including ours, have formulated nonimmunogenic peptides based on the sequence of myelin basic protein (MBP) that bind class II MHC to a much greater extent than the native, encephalitogenic peptides of MBP, and that prevent EAE when given in adjuvant (4-9). We now extend this approach in order to develop TCR. antagonists that would prevent and reverse EAE, when induced by MBP p87-99. The rationale for pursuing inhibitors of the MBP p87-99 follows from some serendipitous findings (10) regarding a major set of TCR rearrangements in multiple sclerosis (MS) brain lesions. Using PCK on reverse-transcribed mRNA, we
Journal of Clinical Investigation, 1993
An epitope present in the 71-90 sequence of basic protein (BP) has been identified as the dominant epitope recognized by most Lewis rat encephalitogenic T cells isolated during experimental autoimmune encephalomyelitis (EAE). In the present study, we investigated the BP epitopes recognized by Lewis rat T cells in naive rats, in rats suffering from acute EAE, and in recovered rats. T cells isolated from the spinal cord lesions and from the lymph nodes were studied using T cell lines and bulk cultures. Virulence of the T cells was assayed by adoptive transfer. We now report that naive and recovered Lewis rats are populated with T cells reactive to a variety of BP epitopes and only a minority are specific for the 71-90 epitope. In contrast, the induction of EAE was associated with a predominance ofT cells reactive to the 71-90 epitope. T cells recovered from naive, diseased, or recovered rats were found to be virulent upon passive transfer. Some of these virulent T cells were specific to BP epitopes other than the 71-90 epitope. There was no major difference in the BP specificities of T cells isolated from the lesions and from the lymph nodes. Thus, natural T cell reactivity to BP is heterogeneous and pathogenicity is not confined to one particular epitope, active disease is characterized by a dominant response to the 71-90 epitope, and recovery is marked by a return to heterogeneity. (J. Clin. Invest. 1993. 92:2199-2206