A central role in the complex immunology of MS is played by activated T lymphocytes. Proper antigenic stimulation, adequate major histocompatibility complex (MHC) coactivation and multiple cytokine signals regulate T-cell activation via the generation of intracellular calcium (Ca2+) transients necessary to up-regulate the genes controlling lymphocyte growth and differentiation. Interferon gamma (IFN-gamma) exerts an autocrine/paracrine control of T-lymphocyte activity and is able to co-mediate most demyelinating events occurring in MS patients. The mechanisms by which IFN-gamma exerts its effects include increased expression of MHC class II molecules on the surface of glial cells and stimulation of macrophage/microglial cell production of molecules toxic to myelin. Most intracellular events regulating these processes in lymphocytes are, however, still unknown. We have reported that in the majority of MS patients T lymphocytes (mainly CD4+) exposed to IFN-gamma show a Ca2+ influx whose ion permeability and pharmacological properties differ from those of all Ca2+ influxes so far described. This IFN-gamma-activated Ca2+ influx, which is probably sustained by a cationic channel, was observed in the majority of patients with MS, but only in a limited number of subjects affected by other neurological, active immune-mediated diseases or healthy control subjects. Moreover, the presence of the influx correlates with clinical and radiological evidence of disease activity and induces T-lymphocyte proliferation even when cells are suboptimally stimulated by activatory stimuli. We conclude that this new IFN-gamma-activated Ca2+ influx seems to be highly specific for MS (especially during its active phase), and could be important for the intracellular regulation of cells involved in demyelination. The presence of the influx in T lymphocytes from MS patients could account for the reported temporal association between infections and clinical relapses.