TY - JOUR
T1 - Upregulated inducible co-stimulator (ICOS) and ICOS-ligand in inclusion body myositis muscle
T2 - Significance for CD8+ T cell cytotoxicity
AU - Schmidt, Jens
AU - Rakocevic, Goran
AU - Raju, Raghavanpillai
AU - Dalakas, Marinos C.
N1 - Funding Information:
We wish to thank Rebekah Granger for her excellent technical assistance, and Roland Martin (Cellular Immunology Section, NINDS) for stimulating discussions. J.S. was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG, Schm 1669/1-1) and by an award from NINDS.
PY - 2004/5
Y1 - 2004/5
N2 - Interactions between inducible co-stimulatory molecule (ICOS) and ICOS-ligand (ICOS-L) are crucial for T-cell co-stimulation, effector cell differentiation and memory CD8+ T-cell activation. Because in the muscle of patients with sporadic inclusion body myositis (sIBM) clonally expanded CD8+ T cells invade major histocompatibility complex (MHC) class I-expressing muscle fibres, we investigated ICOS.ICOS-L interactions and correlated their expression with perforin, a marker for cytotoxic effector function by autoinvasive CD8+ T cells. The mRNA from 20 muscle biopsies of sIBM, 20 non-inflammatory or dystrophic controls, two dermatomyositis (DM) and two polymyositis (PM) patients was reverse transcribed and reamplified by semi-quantitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR), using primers for ICOS, ICOS-L and perforin. The glyceraldehyde 3-phosphate dehydrogenase (GAPDH)-normalized ratio of ICOS, ICOS-L and perforin expression was compared with the degree of endomysial inflammation. Protein expression of ICOS, ICOS-L and perforin was confirmed by immunohistochemistry. We demonstrate that ICOS-L mRNA was upregulated in sIBM (arbitrary units, median ± SEM: 48.6 ± 14.9) compared with controls (6.2 ± 17.8, P < 0.05) and significantly correlated with the expression of ICOS (53.9 ± 16.6 versus 6.7 ± 8.9 in controls, P < 0.001). By triple labelling immunohistochemistry, the CD8+ T cells in sIBM and PM were found to invade ICOS-L- and MHC class I-co-expressing muscle fibres. Among the autoinvasive CD8+ T cells, however, only a subset of ∼5-10% were ICOS positive, and thereby perceptive for ICOS-ICOS-L signalling at the immunological synapse. In contrast, in Duchenne muscular dystrophy and DM, although ICOS and ICOS-L mRNA expression was also increased, the majority of ICOS-L- and ICOS-positive cells were in the perimysial regions and connective tissue. The mRNA for perforin was increased in sIBM (28.1 ± 8.7) compared with controls (4.3 ± 11.2, P = 0.18), and significantly correlated with mRNA of ICOS, ICOS-L and the degree of endomysial inflammation as assessed in coded haematoxylin/eosin tissue sections. By triple immunohistochemical staining and cell counting, perforin granules were found in 71% of the autoinvasive CD8+ T cells that were also ICOS positive. Our data indicate that in sIBM there is upregulation of ICOS·ICOS-L co-stimulatory signalling in association with enhanced perforin expression by the autoinvasive CD8+ T cells. The findings support previous suggestions that in IBM, the muscle fibres have the capacity for antigen presentation, thereby activating a specific subset among the autoinvasive CD8+ T cells to exert a cytotoxic effect. The observations strengthen the immunopathogenesis of sIBM, and offer the basis for future therapeutic interventions targeting ICOS·ICOS-L co-stimulatory interactions.
AB - Interactions between inducible co-stimulatory molecule (ICOS) and ICOS-ligand (ICOS-L) are crucial for T-cell co-stimulation, effector cell differentiation and memory CD8+ T-cell activation. Because in the muscle of patients with sporadic inclusion body myositis (sIBM) clonally expanded CD8+ T cells invade major histocompatibility complex (MHC) class I-expressing muscle fibres, we investigated ICOS.ICOS-L interactions and correlated their expression with perforin, a marker for cytotoxic effector function by autoinvasive CD8+ T cells. The mRNA from 20 muscle biopsies of sIBM, 20 non-inflammatory or dystrophic controls, two dermatomyositis (DM) and two polymyositis (PM) patients was reverse transcribed and reamplified by semi-quantitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR), using primers for ICOS, ICOS-L and perforin. The glyceraldehyde 3-phosphate dehydrogenase (GAPDH)-normalized ratio of ICOS, ICOS-L and perforin expression was compared with the degree of endomysial inflammation. Protein expression of ICOS, ICOS-L and perforin was confirmed by immunohistochemistry. We demonstrate that ICOS-L mRNA was upregulated in sIBM (arbitrary units, median ± SEM: 48.6 ± 14.9) compared with controls (6.2 ± 17.8, P < 0.05) and significantly correlated with the expression of ICOS (53.9 ± 16.6 versus 6.7 ± 8.9 in controls, P < 0.001). By triple labelling immunohistochemistry, the CD8+ T cells in sIBM and PM were found to invade ICOS-L- and MHC class I-co-expressing muscle fibres. Among the autoinvasive CD8+ T cells, however, only a subset of ∼5-10% were ICOS positive, and thereby perceptive for ICOS-ICOS-L signalling at the immunological synapse. In contrast, in Duchenne muscular dystrophy and DM, although ICOS and ICOS-L mRNA expression was also increased, the majority of ICOS-L- and ICOS-positive cells were in the perimysial regions and connective tissue. The mRNA for perforin was increased in sIBM (28.1 ± 8.7) compared with controls (4.3 ± 11.2, P = 0.18), and significantly correlated with mRNA of ICOS, ICOS-L and the degree of endomysial inflammation as assessed in coded haematoxylin/eosin tissue sections. By triple immunohistochemical staining and cell counting, perforin granules were found in 71% of the autoinvasive CD8+ T cells that were also ICOS positive. Our data indicate that in sIBM there is upregulation of ICOS·ICOS-L co-stimulatory signalling in association with enhanced perforin expression by the autoinvasive CD8+ T cells. The findings support previous suggestions that in IBM, the muscle fibres have the capacity for antigen presentation, thereby activating a specific subset among the autoinvasive CD8+ T cells to exert a cytotoxic effect. The observations strengthen the immunopathogenesis of sIBM, and offer the basis for future therapeutic interventions targeting ICOS·ICOS-L co-stimulatory interactions.
KW - Autoimmunity
KW - Co-stimulation
KW - Inclusion body myositis
KW - Muscle inflammation
KW - Perforin
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U2 - 10.1093/brain/awh148
DO - 10.1093/brain/awh148
M3 - Review article
C2 - 15047591
AN - SCOPUS:2442481908
SN - 0006-8950
VL - 127
SP - 1182
EP - 1190
JO - Brain
JF - Brain
IS - 5
ER -