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 re sponse 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-media ted mobilization of intracellular calcium together with a more global block in T cell receptor-independent capacitative calcium entry (CCE). The proli ferative resp on se of these antigen-specific T-H cells to anti-CD3, anti-C D28 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 throu gh a CD69-coupled G protein and required calcium-bound calmodulin and calci neurin. These data reveal critical changes in the responsiveness of antigen -specific T-H cells and provide evidence of new mechanisms for the regulati on of antigen-specific T-H cell development in vivo.