Upregulated inducible co-stimulator (ICOS) and ICOS-ligand in inclusion body myositis muscle: significance for CD8+ T cell cytotoxicity.
2004
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.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
41
References
80
Citations
NaN
KQI