Target-Cell Contact Activates a Highly Selective Capacitative Calcium Entry Pathway in Cytotoxic T Lymphocytes

doi:10.1083/jcb.148.3.603

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© The Rockefeller University Press, 0021-9525/2000//603 $5.00
The Journal of Cell Biology, Volume 148, Number 3, , 2000 603-614

Original Article

Target-Cell Contact Activates a Highly Selective Capacitative Calcium Entry Pathway in Cytotoxic T Lymphocytes

Adam Zweifach^a

^a Department of Physiology and Biophysics and Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado 80262
Department of Physiology and Biophysics, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262.(303) 315-8110(303) 315-5007

adam.zweifach{at}uchsc.edu

Calcium influx is critical for T cell activation. Evidence hasbeen presented that T cell receptor–stimulated calciuminflux in helper T lymphocytes occurs via channels activatedas a consequence of depletion of intracellular calcium stores,a mechanism known as capacitative Ca²⁺ entry (CCE). However,two key questions have not been addressed. First, the mechanismof calcium influx in cytotoxic T cells has not been examined.While the T cell receptor–mediated early signals in helperand cytotoxic T cells are similar, the physiology of the cellsis strikingly different, raising the possibility that the mechanismof calcium influx is also different. Second, contact of T cellswith antigen-presenting cells or targets involves a host ofintercellular interactions in addition to those between antigen–MHCand the T cell receptor. The possibility that calcium influxpathways in addition to those activated via the T cell receptormay be activated by contact with relevant cells has not beenaddressed. We have used imaging techniques to show that target-cell–stimulatedcalcium influx in CTLs occurs primarily through CCE. We investigatedthe permeability of the CTL influx pathway for divalent cations,and compared it to the permeability of CCE in Jurkat human leukemicT cells. CCE in CTLs shows a similar ability to discriminatebetween calcium, barium, and strontium as CCE in Jurkat humanleukemic T lymphocytes, where CCE is likely to mediated by Ca²⁺release–activated Ca²⁺ current (CRAC) channels, suggestingthat CRAC channels also underlie CCE in CTLs. These resultsare the first determination of the mechanism of calcium influxin cytotoxic T cells and the first demonstration that cell contact–mediatedcalcium signals in T cells occur via depletion-activated channels.

Key Words: CTL • Ca²⁺ release–activated Ca²⁺ • current • Fura-2 • granule exocytosis • perforin

Abbreviations used in this paper: APC, antigen-presenting cell;BLT, N-(-benzyloxycarbonyl-L-lysine thiobenzyl ester); [Ca²⁺]_i,intracellular calcium; Ca²⁺₀, extracellular Ca²⁺; CCE, capacitativeCa²⁺ entry; CRAC, Ca²⁺ release–activated Ca²⁺ current;CTLs, cytotoxic T cells; DTNB, 5,5'-dithio-bis-(2-nitrobenzioicacid); IP₃, inositol 1,4,5 trisphosphate; PKC, protein kinaseC; PMA, phorbol myristate acetate; SOC, store-operated Ca²⁺channel; TCR, T cell receptor; TG, thapsigargin.

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