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Interferon-gamma induces T lymphocyte proliferation in multiple sclerosis via a Ca(2+)-dependent mechanism
G Martino1, L Moiola, E Brambilla
1Department of Biotechnology (DIBIT), San Raffaele Scientific Institute, Milan, Italy.
Insights
Multiple sclerosis (MS) T lymphocytes show abnormal calcium influx and preactivation, leading to increased proliferation. Interferon-gamma further boosts proliferation in these preactivated MS T cells, suggesting a key mechanism in the disease.
Area of Science:
- Immunology
- Neuroscience
- Cell Biology
Background:
- Intracellular mechanisms of T lymphocyte activation in multiple sclerosis (MS) remain unclear.
- Interferon-gamma (IFN-γ) activates a novel calcium (Ca2+) influx in T lymphocytes from MS patients, elevating intracellular Ca2+ ([Ca2+]i).
- Ca2+ is a critical second messenger regulating T lymphocyte activation gene transcription.
Purpose of the Study:
- To investigate how elevated [Ca2+]i, due to a specific Ca2+ influx, impacts T lymphocyte proliferation in relapsing-remitting MS (RR-MS) patients.
- To compare T lymphocyte behavior in influx-positive RR-MS patients, influx-negative RR-MS patients, and healthy donors.
Main Methods:
- Assessed T lymphocyte proliferation in response to phytohemagglutinin (PHA) stimulation.
- Measured intracellular Ca2+ ([Ca2+]i) levels in T lymphocytes.
- Investigated the effect of IFN-γ combined with PHA on T lymphocyte proliferation in different patient groups and controls.
Main Results:
- A significant correlation between [Ca2+]i levels and proliferation rate was observed in healthy controls.
- T lymphocytes from RR-MS patients exhibited proliferation at lower PHA doses (1 μg/ml) than healthy controls, indicating preactivation.
- IFN-γ combined with suboptimal PHA doses significantly increased proliferation in influx-positive MS T cells compared to PHA alone.
Conclusions:
- T lymphocytes from MS patients display a state of preactivation characterized by enhanced proliferation.
- The novel IFN-γ-activated Ca2+ influx may play a significant role in the aberrant T lymphocyte activation observed in MS.
- Understanding these mechanisms could offer new therapeutic targets for MS.
Abstract:
The intracellular mechanisms underlying T lymphocyte activation leading to demyelination in multiple sclerosis (MS) have not yet been clarified. We have recently reported that interferon (IFN)-gamma activates a novel trans-plasmalemma Ca2+ influx on T lymphocytes (mainly CD4+) from patients with MS which induces intracellular Ca2+ ([Ca2+]i) elevation. Since Ca2+ is an essential second messenger in regulating transcription of T lymphocyte activation genes, we have evaluated how [Ca2+]i elevation due to the activity of this particular influx affects T lymphocyte proliferative behaviour in 12 influx-positive relapsing-remitting MS (RR-MS) patients. Fourteen influx-negative RR-MS patients and 14 healthy donors were used as controls. In lymphocytes from healthy controls, a significant correlation (r = 0.62; P < 0.001) was found between [Ca2+]i levels and proliferation rate after phytohemagglutinin (PHA) stimulation. Sustained proliferation was induced in T lymphocytes by > or = 10 micrograms/ml of PHA, a dose leading to a [Ca2+]i increase of at least 45% over basal level. Similar [Ca2+]i elevations were obtained when > or = 10 micrograms/ml of PHA were used on cells from RR-MS patients. However, T lymphocytes from RR-MS patients, but not from healthy donors, proliferated also in response to 1 micrograms/ml of PHA, indicating a state of preactivation. Moreover, 1 microgram/ml of PHA used in combination with suboptimal doses of IFN-gamma (5 UI/ml) doubled the proliferation rate of influx-positive MS cells, but not influx-negative MS cells or cells from healthy donors compared to the values obtained using PHA alone (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)