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TCR Signaling via ZAP-70 Induced by CD3 Stimulation is More Active Under Acidic Conditions

Xin Wang, Kenta Hatatani, Yirong Sun, Toshihiko Fukamachi, Hiromi Saito and Hiroshi Kobayashi

Although the pH values of blood and tissues are usually maintained in a narrow range around 7.4, some diseased areas, such as cancer nests, inflammatory loci, and infarction areas, are acidified. In the present study, the effect of extracellular acidic pH on TCR signaling was examined with human acute leukemia T cell line Jurkat cells because T cell infiltration is often observed in acidic diseased areas. The phosphorylation levels of CD3-ξ ZAP-70, and PLC-γ1 induced by OKT-3, anti-CD3 antibody, were higher at pH 6.3 than those at pH 7.6. The activation of PLC-γ1 induced by OKT-3 was further increased by the co-stimulation with CD28.6, anti- CD28 antibody, at pH 7.6, but not at pH 6.3. The level of cytosolic free calcium ions was increased to a higher level by the addition of OKT-3 at pH 6.3, compared with that by the addition of OKT-3 plus CD28.6 at pH 7.6. Further addition of CD28.6 decreased the level of cytosolic free calcium ions induced by OKT-3 at pH 6.3. The Ca2+ mobilization was strongly inhibited by BTP2, a potent inhibitor of Ca2+ channels in the plasma membrane, at pH 7.6, while the inhibition was weak at pH 6.3. The Ca2+ mobilization at pH 6.3 was dependent on ZAP-70 and LAT, but not SLP-76. The activation of ERK and p38 increased as pH decreased. No activation of ERK2 in the presence of OKT-3 was observed in the Jurkat mutant deficient in ZAP-70 at pH 6.3, while ERK1 was activated by the addition
of OKT-3 in this mutant. The expression of IL-2 was not induced by OKT-3 or OKT-3 plus CD28.6 at pH 6.3. These results suggest that the TCR signaling initiated by CD3 stimulation is more active at acidic pH in Jurkat cells and its pathway is different in parts under different pH conditions.