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Intracellular concentrations of Ca2+ modulate the strength of signal and alter the outcomes of cytotoxic T‐lymphocyte antigen‐4 (CD152)–CD80/CD86 interactions in CD4+ T lymphocytes

The costimulatory receptors CD28 and cytotoxic T‐lymphocyte antigen (CTLA)‐4 and their ligands, CD80 and CD86, are expressed on T lymphocytes; however, their functional roles during T cell–T cell interactions are not well known. The consequences of blocking CTLA‐4–CD80/CD86 interactions on purified mouse CD4+ T cells were studied in the context of the strength of signal (SOS). CD4+ T cells were activated with phorbol 12‐myristate 13‐acetate (PMA) and different concentrations of a Ca2+ ionophore, Ionomycin (I), or a sarcoplasmic Ca2+ ATPase inhibitor, Thapsigargin (TG). Increasing concentrations of I or TG increased the amount of interleukin (IL)‐2, reflecting the conversion of a low to a high SOS. During activation with PMA and low amounts of I, intracellular concentrations of calcium ([Ca2+]i) were greatly reduced upon CTLA‐4–CD80/CD86 blockade. Further experiments demonstrated that CTLA‐4–CD80/CD86 interactions reduced cell cycling upon activation with PMA and high amounts of I or TG (high SOS) but the opposite occurred with PMA and low amounts of I or TG (low SOS). These results were confirmed by surface T‐cell receptor (TCR)–CD3 signalling using a low SOS, for example soluble anti‐CD3, or a high SOS, for example plate‐bound anti‐CD3. Also, CTLA‐4–CD80/CD86 interactions enhanced the generation of reactive oxygen species (ROS). Studies with catalase revealed that H2O2 was required for IL‐2 production and cell cycle progression during activation with a low SOS. However, the high amounts of ROS produced during activation with a high SOS reduced cell cycle progression. Taken together, these results indicate that [Ca2+]i and ROS play important roles in the modulation of T‐cell responses by CTLA‐4–CD80/CD86 interactions.