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Differential Ca²⁺ Influx, K_Ca Channel Activity, and Ca²⁺ Clearance Distinguish Th1 and Th2 Lymphocytes¹

Department of Physiology and Biophysics, University of California, Irvine, CA 92697

In Th1 and Th2 lymphocytes, activation begins with identical stimuli but results in the production of different cytokines. The expression of some cytokine genes is differentially induced according to the amplitude and pattern of Ca²⁺ signaling. Using fura- 2 Ca²⁺ imaging of murine Th1 and Th2 clones, we observed that the Ca²⁺ rise elicited following store depletion with thapsigargin is significantly lower in Th2 cells than in Th1 cells. Maximal Ca²⁺ influx rates and whole-cell Ca²⁺ currents showed that both Th1 and Th2 cells express indistinguishable Ca²⁺-release-activated Ca²⁺ channels. Therefore, we investigated other mechanisms controlling the concentration of intracellular Ca²⁺, including K⁺ channels and Ca²⁺ clearance from the cytosol. Whole-cell recording demonstrated that there is no distinction in the amplitudes of voltage-gated K⁺ currents in the two cell types. Ca²⁺-activated K⁺ (K_Ca) currents, however, were significantly smaller in Th2 cells than in Th1 cells. Pharmacological equalization of Ca²⁺-activated K⁺ currents in the two cell types reduced but did not completely eliminate the difference between Th1 and Th2 Ca²⁺ responses, suggesting divergence in an additional Ca²⁺ regulatory mechanism. Therefore, we analyzed Ca²⁺ clearance from the cytosol of both cell types and found that Th2 cells extrude Ca²⁺ more quickly than Th1 cells. The combination of a faster Ca²⁺ clearance mechanism and smaller Ca²⁺-activated K⁺ currents in Th2 cells accounts for the lower Ca²⁺ response of Th2 cells compared with Th1 cells.

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