Antigen-dependent selection of T cells that are able to efficiently regulate free cytoplasmic Ca2+ levels

In T helper cells, the process of memory acquisition is reflected in the expression of phenotypic markers. However, little is known regarding the functional changes that occurred in T helper cells selected after a primary Ag-specific response. We now present data that indicate that such T helper cells acquire the ability to down-regulate high concentrations of free cytoplasmic Ca2+. This property renders them resistant to intense inductive stimuli, such as high concentrations of ionomycin. The accumulation of cells that display this ability parallels the progressive proliferative enrichment of Ag-specific T cells and correlates with the surface expression of the CD45RB(low) isoform. As previously shown, persistent high levels of cytoplasmic Ca2+ are responsible for death via apoptosis in virgin T cells. In contrast, the ability to regulate cytosolic Ca2+ allows survival and clonal expansion. We suggest that memory T cells behave differently from virgin T cells when interacting with Ag-presenting B cells (as reported by others) because they have acquired this new physiologic property. Ag-presenting B cells deliver an intense stimulatory signal to T cells because of a high multiplicity of cognate interactions. Thus, Ag-driven T cell proliferation results in the selection of "resistant" T helper cells that can be successfully stimulated by memory B cells. In contrast, naive T cells, which cannot modulate high levels of cytosolic Ca2+, are deleted as a consequence of Ag presentation by B cells.