Calcium transport is critical for the activation of transcription pathways that drive T cell proliferation and function. On page 651, Feske and colleagues show that Ca2+ release–activated Ca2+ (CRAC) channels in the plasma membrane are the major, if not only, pathway for T cell receptor–activated calcium influx in T cells. The mechanism of activation and identity of these CRAC channels continues to elude researchers.

The authors analyzed channels in T cells from patients with a form of severe congenital immunodeficiency (SCID) that is characterized by impaired T cell activation and a near total lack of calcium influx. Using electrophysiological techniques, they showed that the lack of calcium influx was due to a complete failure of CRAC channel opening, and not a consequence of dysregulated intracellular calcium stores or aberrant expression of other suspected ion channels. The authors believe that the CRAC channels are present in the patients' T cells but that their activation is somehow impaired.

The specificity and severity of the defect in T cells from the SCID patients provide a powerful tool to pinpoint the identity of the CRAC channel and determine its mode of activation. The authors are now using positional cloning approaches and genetic complementation to try to isolate the underlying molecular components.