Cleavage of transaldolase by granzyme B causes the loss of enzymatic activity with retention of antigenicity for multiple sclerosis patients

Brian Niland, Gabriella Miklossy, Katalin Banki, William E. Biddison, Livia A Casciola Rosen, Antony Rosen, Denis Martinvalet, Judy Lieberman, Andras Perl

Research output: Contribution to journalArticle

Abstract

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS resulting from a progressive loss of oligodendrocytes. Transaldolase (TAL) is expressed at selectively high levels in oligodendrocytes of the brain, and postmortem sections show concurrent loss of myelin basic protein and TAL from sites of demyelination. Infiltrating CD8+ CTLs are thought to play a key role in oligodendrocyte cell death. Cleavage by granzyme B (GrB) is predictive for autoantigenicity of self-proteins, thereby further implicating CTL-induced death in the initiation and propagation of autoimmunity. The precursor frequency and CTL activity of HLA-A2-restricted TAL 168-176-specific CD8+ T cells is increased in MS patients. In this paper, we show that TAL, but not myelin basic protein, is specifically cleaved by human GrB. The recognition site of GrB that resulted in the cleavage of a dominant TAL fragment was mapped to a VVAD motif at aa residue 27 by N-terminal sequencing and confirmed by site-directed mutagenesis. The major Cterminal GrB cleavage product, residues 28-337, had no enzymatic activity but retained the antigenicity of full-length TAL, effectively stimulating the proliferation and CTL activity of PBMCs and of CD8+ T cell lines from patients with MS. Sera of MS patients exhibited similar binding affinity to wild-type and GrB-cleaved TAL. Because GrB mediates the killing of target cells and cleavage by GrB is predictive of autoantigen status of self proteins, GrB-cleaved TAL-specific T cell-mediated cytotoxicity may contribute to the progressive destruction of oligodendrocytes in patients with MS.

Original languageEnglish (US)
Pages (from-to)4025-4032
Number of pages8
JournalJournal of Immunology
Volume184
Issue number7
DOIs
StatePublished - Apr 1 2010

Fingerprint

Transaldolase
Granzymes
Multiple Sclerosis
Oligodendroglia
Myelin Basic Protein
T-Lymphocytes
CNS Demyelinating Autoimmune Diseases
HLA-A2 Antigen
Autoantigens
Demyelinating Diseases
Site-Directed Mutagenesis
Autoimmunity
Cell Death

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Cleavage of transaldolase by granzyme B causes the loss of enzymatic activity with retention of antigenicity for multiple sclerosis patients. / Niland, Brian; Miklossy, Gabriella; Banki, Katalin; Biddison, William E.; Casciola Rosen, Livia A; Rosen, Antony; Martinvalet, Denis; Lieberman, Judy; Perl, Andras.

In: Journal of Immunology, Vol. 184, No. 7, 01.04.2010, p. 4025-4032.

Research output: Contribution to journalArticle

Niland, Brian ; Miklossy, Gabriella ; Banki, Katalin ; Biddison, William E. ; Casciola Rosen, Livia A ; Rosen, Antony ; Martinvalet, Denis ; Lieberman, Judy ; Perl, Andras. / Cleavage of transaldolase by granzyme B causes the loss of enzymatic activity with retention of antigenicity for multiple sclerosis patients. In: Journal of Immunology. 2010 ; Vol. 184, No. 7. pp. 4025-4032.
@article{02dbb6a8d69c4b75bc8320ad3da4e9f0,
title = "Cleavage of transaldolase by granzyme B causes the loss of enzymatic activity with retention of antigenicity for multiple sclerosis patients",
abstract = "Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS resulting from a progressive loss of oligodendrocytes. Transaldolase (TAL) is expressed at selectively high levels in oligodendrocytes of the brain, and postmortem sections show concurrent loss of myelin basic protein and TAL from sites of demyelination. Infiltrating CD8+ CTLs are thought to play a key role in oligodendrocyte cell death. Cleavage by granzyme B (GrB) is predictive for autoantigenicity of self-proteins, thereby further implicating CTL-induced death in the initiation and propagation of autoimmunity. The precursor frequency and CTL activity of HLA-A2-restricted TAL 168-176-specific CD8+ T cells is increased in MS patients. In this paper, we show that TAL, but not myelin basic protein, is specifically cleaved by human GrB. The recognition site of GrB that resulted in the cleavage of a dominant TAL fragment was mapped to a VVAD motif at aa residue 27 by N-terminal sequencing and confirmed by site-directed mutagenesis. The major Cterminal GrB cleavage product, residues 28-337, had no enzymatic activity but retained the antigenicity of full-length TAL, effectively stimulating the proliferation and CTL activity of PBMCs and of CD8+ T cell lines from patients with MS. Sera of MS patients exhibited similar binding affinity to wild-type and GrB-cleaved TAL. Because GrB mediates the killing of target cells and cleavage by GrB is predictive of autoantigen status of self proteins, GrB-cleaved TAL-specific T cell-mediated cytotoxicity may contribute to the progressive destruction of oligodendrocytes in patients with MS.",
author = "Brian Niland and Gabriella Miklossy and Katalin Banki and Biddison, {William E.} and {Casciola Rosen}, {Livia A} and Antony Rosen and Denis Martinvalet and Judy Lieberman and Andras Perl",
year = "2010",
month = "4",
day = "1",
doi = "10.4049/jimmunol.0804174",
language = "English (US)",
volume = "184",
pages = "4025--4032",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "7",

}

TY - JOUR

T1 - Cleavage of transaldolase by granzyme B causes the loss of enzymatic activity with retention of antigenicity for multiple sclerosis patients

AU - Niland, Brian

AU - Miklossy, Gabriella

AU - Banki, Katalin

AU - Biddison, William E.

AU - Casciola Rosen, Livia A

AU - Rosen, Antony

AU - Martinvalet, Denis

AU - Lieberman, Judy

AU - Perl, Andras

PY - 2010/4/1

Y1 - 2010/4/1

N2 - Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS resulting from a progressive loss of oligodendrocytes. Transaldolase (TAL) is expressed at selectively high levels in oligodendrocytes of the brain, and postmortem sections show concurrent loss of myelin basic protein and TAL from sites of demyelination. Infiltrating CD8+ CTLs are thought to play a key role in oligodendrocyte cell death. Cleavage by granzyme B (GrB) is predictive for autoantigenicity of self-proteins, thereby further implicating CTL-induced death in the initiation and propagation of autoimmunity. The precursor frequency and CTL activity of HLA-A2-restricted TAL 168-176-specific CD8+ T cells is increased in MS patients. In this paper, we show that TAL, but not myelin basic protein, is specifically cleaved by human GrB. The recognition site of GrB that resulted in the cleavage of a dominant TAL fragment was mapped to a VVAD motif at aa residue 27 by N-terminal sequencing and confirmed by site-directed mutagenesis. The major Cterminal GrB cleavage product, residues 28-337, had no enzymatic activity but retained the antigenicity of full-length TAL, effectively stimulating the proliferation and CTL activity of PBMCs and of CD8+ T cell lines from patients with MS. Sera of MS patients exhibited similar binding affinity to wild-type and GrB-cleaved TAL. Because GrB mediates the killing of target cells and cleavage by GrB is predictive of autoantigen status of self proteins, GrB-cleaved TAL-specific T cell-mediated cytotoxicity may contribute to the progressive destruction of oligodendrocytes in patients with MS.

AB - Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS resulting from a progressive loss of oligodendrocytes. Transaldolase (TAL) is expressed at selectively high levels in oligodendrocytes of the brain, and postmortem sections show concurrent loss of myelin basic protein and TAL from sites of demyelination. Infiltrating CD8+ CTLs are thought to play a key role in oligodendrocyte cell death. Cleavage by granzyme B (GrB) is predictive for autoantigenicity of self-proteins, thereby further implicating CTL-induced death in the initiation and propagation of autoimmunity. The precursor frequency and CTL activity of HLA-A2-restricted TAL 168-176-specific CD8+ T cells is increased in MS patients. In this paper, we show that TAL, but not myelin basic protein, is specifically cleaved by human GrB. The recognition site of GrB that resulted in the cleavage of a dominant TAL fragment was mapped to a VVAD motif at aa residue 27 by N-terminal sequencing and confirmed by site-directed mutagenesis. The major Cterminal GrB cleavage product, residues 28-337, had no enzymatic activity but retained the antigenicity of full-length TAL, effectively stimulating the proliferation and CTL activity of PBMCs and of CD8+ T cell lines from patients with MS. Sera of MS patients exhibited similar binding affinity to wild-type and GrB-cleaved TAL. Because GrB mediates the killing of target cells and cleavage by GrB is predictive of autoantigen status of self proteins, GrB-cleaved TAL-specific T cell-mediated cytotoxicity may contribute to the progressive destruction of oligodendrocytes in patients with MS.

UR - http://www.scopus.com/inward/record.url?scp=77951643062&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951643062&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.0804174

DO - 10.4049/jimmunol.0804174

M3 - Article

C2 - 20194725

AN - SCOPUS:77951643062

VL - 184

SP - 4025

EP - 4032

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 7

ER -