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Lysis of human glial cells by major histocompatibility complex-unrestricted CD4+ cytotoxic lymphocytes
T C Ruijs1, K Louste, E A Brown
1Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Quebec, Canada.
Insights
Non-major histocompatibility complex (MHC)-restricted CD4+ T lymphocytes can lyse human glial cells, including oligodendrocytes, astrocytes, and microglia. This cell-mediated injury may depend on effector:target cell contact.
Area of Science:
- Immunology
- Neuroscience
- Cell Biology
Background:
- CD4+ T lymphocytes play crucial roles in immune responses.
- Glial cells are essential for central nervous system function.
- Understanding T-cell interactions with glial cells is vital for neuroinflammatory diseases.
Purpose of the Study:
- To investigate the lysis of human glial cells by non-major histocompatibility complex (MHC)-restricted CD4+ T lymphocytes.
- To determine the mechanisms and conditions underlying this glial cell injury.
Main Methods:
- Activation of CD4+ T lymphocytes under long-term limiting dilution or short-term bulk culture conditions.
- Assessment of glial cell lysis using 51Cr-release assays with varying effector:target cell ratios.
- Investigation of the role of tumor necrosis factor (TNF)-alpha and cell contact in T-cell-mediated lysis.
Main Results:
- Specific effector:target cell ratio-dependent lysis of oligodendrocytes (OGCs), astrocytes, and microglia by CD4+ T lymphocytes was observed.
- Lysis occurred in 18-h but not 5-h assays, suggesting a time-dependent mechanism.
- The lysis was not inhibited by anti-TNF-alpha antibodies, indicating a TNF-independent pathway, and may be enhanced by cell contact.
Conclusions:
- Non-antigen, non-MHC-restricted CD4+ T cells can mediate injury to human glial cells.
- This glial cell damage appears to be independent of TNF-alpha and potentially dependent on effector:target cell contact.
Abstract:
We have investigated lysis of cultured human glial cells by non-major histocompatibility complex (MHC)-restricted or 'promiscuous' CD(4+)-T lymphocytes, activated either under relatively long-term limiting dilution culture conditions in the presence of phytohemagglutinin (PHA) and interleukin (IL)-2, or under short-term PHA-activated bulk culture conditions. Specific effector:target cell ratio-dependent lysis of oligodendrocytes (OGCs) by CD4+ T lymphocytes, generated under both of the above conditions, was observed in an 18-h 51Cr-release assay, but not in a 5-h assay. The extent of CD4 T-cell-mediated OGC lysis was less than for the tumor necrosis factor (TNF)-alpha-sensitive cell line U937, but greater than for TNF-resistant cell lines (K562, EL4). The effect could not be reproduced by T-cell culture supernatants or by high concentrations of recombinant TNF-alpha or beta. Anti-TNF-alpha antibody did not inhibit CD4-mediated lysis of OGC or U937 cells, but did inhibit U937 lysis induced by recombinant TNF-alpha, added in amounts exceeding those secreted by CD4 T cells. Human astrocytes and microglia were also susceptible to CD4+ T-cell-mediated lysis. Our results suggest that non-antigen non-MHC-restricted CD4+ T-cell-mediated injury of human glial cells can occur and may be dependent or enhanced by effector:target cell contact.