Fig. 5.

Roles of Ca²⁺ signalling in diverse aspects of T cell activation. (A) Gradual levels of store-operated Ca²⁺ entry generated by genetic modifications. Left-CRAC channel activity was measured in effector CD4⁺ T cells from wild type (WT), Orai1 heterozygous (Orai1^+/−) and Orai1-deficient (Orai1^−/−) mice after store depletion with thapsigargin (TG) in the presence of extracellular solution containing 0.5 and 2 mM Ca²⁺. Right-CRAC channel activity was measured in Orai1^−/− CD4⁺ T cells transduced with retroviruses expressing empty vector (vector, blue trace), wild type (Orai1^WT, black trace) or dominant negative mutant of Orai1 (Orai1^E106Q). Data modified from article originally published in (Kim et al., 2011). (B) Ca²⁺ requirement for T cell death, cytokine production and proliferation differs. T cell proliferation does not need high Ca²⁺. Instead, excessive Ca²⁺ concentrations induce cell death and anergy in T cells. Therefore, T cell proliferation requires moderate intracellular Ca²⁺ concentrations as observed in Orai1-deficient (Orai1^−/−) T cells and a further reduction in [Ca²⁺]_i by overexpression of dominant negative Orai1 (DN-Orai1) in Orai1^−/− T cells inhibits proliferation. Thus the threshold of [Ca²⁺]_i necessary for proliferation is much lower than that for cell death and anergy. However, cytokine production gradually increases with increase in [Ca²⁺]_i, with DN-Orai1 cells showing minimal cytokine production and Orai1^+/+ cells showing maximal cytokine levels. Thus, the pattern of Ca²⁺ signalling can modulate the outcomes of T cell fates such as cytokine production, proliferation, anergy, and cell death in a digital or analogue manner.