The calcium current activated by T cell receptor and store depletion in human lymphocytes is absent in a primary immunodeficiency.
Stimulation of antigen receptors of lymphocytes triggers a transitory release of Ca2+ from internal stores and the opening of a transmembrane Ca2+ conductive pathway. The latter underlies the sustained increase of intracellular free calcium concentration, and it seems to be a key event in the Ca(2+)-dependent biochemical cascade leading to T cell proliferation. Alternatively, pharmacological depletion of internal stores by itself activates Ca2+ influx. This has led to the hypothesis that antigen-triggered Ca2+ influx is secondary to Ca2+ release from internal stores. However, the precise relationship between antigen and Ca2+ release-activated Ca2+ currents remains unclear, particularly since neither of them has been electrophysiologically recorded in normal lymphocytes. Using the whole-cell and the perforated configurations of the patch clamp technique on peripheral blood lymphocytes, we found that a low amplitude Ca(2+)-selective current was triggered when intracellular stores were depleted by stimuli such as the intracellular perfusion of inositol triphosphate or thapsigargin and the extracellular perfusion of ionomycin. A similar current was elicited by the cross-linking of the T cell receptor-CD3 complex. This current displayed an inward rectification below 0 mV and was completely blocked by the divalent cation Cd2+. It was very selective for Ca2+ over Na+ and insensitive to changes in chloride concentration. The physiological relevance of this conductance was investigated with the analysis of abnormal Ca2+ signaling in lymphocytes from a patient suffering from a primary immunodeficiency associated with a defective T cell proliferation. Using fura-2 video imaging, an absence of Ca2+ influx was established in the patient's lymphocytes, whereas the Ca2+ release from internal stores was normal. This was the case whether cells were stimulated physiologically through their antigen receptors or with store depleting pharmacological agents. Most importantly, no Ca(2+)-selective current was elicited in these cells. Our data strongly suggest that the Ca2+ release-activated current underlies the sustained Ca2+ influx during antigenic stimulation and that it plays a key role in the immune function.
Partiseti
M
M
INSERM U261, Institut Pasteur, Paris, France.
Le Deist
F
F
Hivroz
C
C
Fischer
A
A
Korn
H
H
Choquet
D
D
D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology / Q000378:metabolism*; D007223:Infant; D008297:Male; D008564:Membrane Potentials; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism* / Q000502:physiology; D014741:Video Recording
D011948:Receptors, Antigen, T-Cell; D002118:Calcium