Clonal diversity of basic protein specific T cells in Lewis rats recovered from experimental autoimmune encephalomyelitis

Vainiene, M.; Offner, Halina; Morrison, William J.; Wilkinson, Miles; Vandenbark, Arthur A.

doi:10.1016/0165-5728(91)90108-j

Cited by 20 publications

(19 citation statements)

References 30 publications

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“…Our present data document that T cell epitopes can be located in virtually all regions of the human MBP se- consistent with the data presented in a previous study (31), in which reactivity to a similar peptide (amino acids [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] (36,37). Our analysis of HLA restriction demonstrates that the number of HLA class II products presenting MBP epitopes was large.…”

Section: Discussionsupporting

confidence: 79%

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Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones.

Meinl¹,

Weber²,

Drexler³

et al. 1993

J. Clin. Invest.

138

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The human T cell response to the myelin basic protein (MBP) has been studied with respect to T cell receptor (TCR) peptide of which is currently being used in a clinical trial for treatment of MS patients, was expressed by only one of our TCL. However, within this complex pattern of MBP-specific T cell responses, a minority of MS patients were found to exhibit a more restricted response with respect to their TCL epitope specificity. In these patients 75-87% of the TCL responded to a single, patient-specific cluster of immunodominant T cell epitopes located within a small (20-amino acid) domain of MBP.These nested clusters of immunodominant epitopes were noted within the amino acids 80-105, 108-131, and 131-153. The T cell response to the immunodominant epitopes was not monoclonal, but heterogeneous, with respect to fine specificity, TCR usage, and even HLA restriction. In one patient (H.K.), this

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Section: Discussionsupporting

confidence: 79%

“…The epitope dominance in Lewis rats (42,43) and PL/J mice (44) has two features, which may be relevant to understand the epitope dominance observed in our MS patients. First, we found recently that in the Lewis rat, epitope dominance is not a property of the naive T cell repertoire, but develops upon immunization in vivo.…”

Section: Discussionmentioning

confidence: 99%

Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones.

Meinl¹,

Weber²,

Drexler³

et al. 1993

J. Clin. Invest.

138

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“…Most T cells induced after immunization with Gp-MBP 72-89 are RT1.B restricted, but are only weakly stimulated with Rt-MBP 72-89 (32). Conversely, most T cells induced after immunization with Rt-MBP 72-89 are also RT1.B restricted, but can still be stimulated efficiently with Gp-MBP 72-89 (33).…”

Section: Discussionmentioning

confidence: 95%

Recombinant TCR Ligand Induces Early TCR Signaling and a Unique Pattern of Downstream Activation

Wang

Mooney

Meza-Romero

et al. 2003

The Journal of Immunology

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Recombinant TCR ligands (RTLs) consisting of covalently linked α1 and β1 domains of MHC class II molecules tethered to specific antigenic peptides represent minimal TCR ligands. In a previous study we reported that the rat RTL201 construct, containing RT1.B MHC class II domains covalently coupled to the encephalitogenic guinea pig myelin basic protein (Gp-MBP72–89) peptide, could prevent and treat actively and passively induced experimental autoimmune encephalomyelitis in vivo by selectively inhibiting Gp-MBP72–89 peptide-specific CD4+ T cells. To evaluate the inhibitory signaling pathway, we tested the effects of immobilized RTL201 on T cell activation of the Gp-MBP72–89-specific A1 T cell hybridoma. Activation was exquisitely Ag-specific and could not be induced by RTL200 containing the rat MBP72–89 peptide that differed by a threonine for serine substitution at position 80. Partial activation by RTL201 included a CD3ζ p23/p21 ratio shift, ZAP-70 phosphorylation, calcium mobilization, NFAT activation, and transient IL-2 production. In comparison, anti-CD3ε treatment produced stronger activation of these cellular events with additional activation of NF-κB and extracellular signal-regulated kinases as well as long term increased IL-2 production. These results demonstrate that RTLs can bind directly to the TCR and modify T cell behavior through a partial activation mechanism, triggering specific downstream signaling events that deplete intracellular calcium stores without fully activating T cells. The resulting Ag-specific activation of the transcription factor NFAT uncoupled from the activation of NF-κB or extracellular signal-regulated kinases constitutes a unique downstream activation pattern that accounts for the inhibitory effects of RTL on encephalitogenic CD4+ T cells.

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“…However, this seemingly minor difference in sequence has profound immunological effects in LEW rats, with the Rt-MBP-72-89 peptide possessing about 10-fold less encephalitogenic activity on a molar basis (28,29). Most T cells induced after immunization with Gp-MBP-72-89 are RT1.B restricted, but are only weakly stimulated with Rt-MBP-72-89 (30). Conversely, most T cells induced after immunization with Rt-MBP-72-89 are also RT1.B restricted, but can still be stimulated efficiently with Gp-MBP-72-89 (28).…”

Section: Discussionmentioning

confidence: 95%

Regulation of Encephalitogenic T Cells with Recombinant TCR Ligands

Burrows

Adlard²,

Bebo

et al. 2000

The Journal of Immunology

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We have previously described recombinant MHC class II β1 and α1 domains loaded with free antigenic peptides with potent inhibitory activity on encephalitogenic T cells. We have now produced single-chain constructs in which the peptide Ag is genetically encoded within the same exon as the linked β1 and α1 domains, overcoming the problem of displacement of peptide Ag from the peptide binding cleft. We here describe clinical effects of recombinant TCR ligands (RTLs) comprised of the rat RT1.B β1α1 domains covalently linked to the 72–89 peptide of guinea pig myelin basic protein (RTL-201), to the corresponding 72–89 peptide from rat myelin basic protein (RTL-200), or to cardiac myosin peptide CM-2 (RTL-203). Only RTL-201 possessed the ability to prevent and treat active or passive experimental autoimmune encephalomyelitis. Amelioration of experimental autoimmune encephalomyelitis was associated with a selective inhibition of proliferation response and cytokine production by Ag-stimulated lymph node T cells and a drastic reduction in the number of encephalitogenic and recruited inflammatory cells infiltrating the CNS. The exquisitely selective inhibition could be observed between molecules that differ by a single methyl group (the single amino acid residue difference between RTL-200 (threonine) and RTL-201 (serine) at position 80 of the myelin basic protein peptide). These novel RTLs provide a platform for developing potent and selective human diagnostic and therapeutic agents for treatment of autoimmune disease.

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Clonal diversity of basic protein specific T cells in Lewis rats recovered from experimental autoimmune encephalomyelitis

Cited by 20 publications

References 30 publications

Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones.

Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones.

Recombinant TCR Ligand Induces Early TCR Signaling and a Unique Pattern of Downstream Activation

Regulation of Encephalitogenic T Cells with Recombinant TCR Ligands

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