Regulating T helper cell immunity through antigen responsiveness and calcium entry

We evaluated changes in the signaling potentials and proliferative capacity of single antigen-specific T helper (T-H) cells during a primary immune response to a protein antigen. At the peak of cellular expansion in vivo all antigen-specific T-H cells exhibited a profound block in CD3- and CD4-mediated mobilization of intracellular calcium together with a more global block in T cell receptor-independent capacitative calcium entry (CCE). The proliferative resp on se of these antigen-specific T-H cells to anti-CD3, anti-CD28 and IL-2 was also severely blunted. Cross-linking CD69 on a substantial fraction of CD69(+) antigen-specific T-H cells relieved this block in CCE and restored proliferative capacity in vitro. The CCE rescue operated through a CD69-coupled G protein and required calcium-bound calmodulin and calcineurin. These data reveal critical changes in the responsiveness of antigen-specific T-H cells and provide evidence of new mechanisms for the regulation of antigen-specific T-H cell development in vivo.