Calcium dependence of T cell proliferation following focal stimulation

Clonal T cell expansion through proliferation is a central process of the adaptive immune response. Apoptosis of activated T cells is required to avoid chronic inflammation. T cell proliferation and apoptosis are often analyzed with stimuli that do not induce formation of a functional immunological synapse. Here we analyze the Ca2+ dependence of proliferation and apoptosis in primary human CD4+ T cells following stimulation with anti‐CD3/anti‐CD28‐coated beads, which induce a tight interaction similar to the immunological synapse. We found this focal stimulation to be much more efficient for stimulating IL‐2 production and proliferation than non‐focal TCR stimuli. Surprising little Ca2+ entry through Ca2+ channels was required for T cell proliferation. Transient free intracellular calcium concentration ([Ca2+]i) elevations of up to 220 nM from a baseline level of around 40 nM were sufficient for maximal proliferation in primary human CD4+ T cells. We also show that proliferation was very Ca2+ sensitive in the range 90–120 nM, whereas apoptosis was basically constant for [Ca2+]i levels of 90–120 nM. We conclude that very small changes in [Ca2+]i can dramatically change the ratio between proliferation and apoptosis, thus keeping the balance between overshooting and inefficient immune responses.