CD4 super( +) and CD8 super( +) T cell-dependent antiviral immunity requires STIM1 and STIM2

Calcium signaling is critical for lymphocyte function, and intracellular Ca super( 2+) concentrations are regulated by store-operated Ca super( 2+) entry (SOCE) through Ca super( 2+) release-activated Ca super( 2+) (CRAC) channels. In patients, loss-of-function mutations in CRAC channel components ORAI1 and STIM1 abolish SOCE and are associated with recurrent and chronic viral infections. Here, using mice with conditional deletion of Stim1 and its homolog Stim2 in T cells, we determined that both components are required for the maintenance of virus-specific memory CD8 super( +) T cells and recall responses following secondary infection. In the absence of STIM1 and STIM2, acute viral infections became chronic. Early during infection, STIM1 and STIM2 were required for the differentiation of naive CD8 super( +) T cells into fully functional cytolytic effector cells and mediated the production of cytokines and prevented cellular exhaustion in viral-specific CD8 super( +) effector T cells. Importantly, memory and recall responses by CD8 super( +) T cells required expression of STIM1 and STIM2 in CD4 super( +) T cells. CD4 super( +) T cells lacking STIM1 and STIM2 were unable to provide "help" to CD8 super( +) T cells due to aberrant regulation of CD40L expression. Together, our data indicate that STIM1, STIM2, and CRAC channel function play distinct but synergistic roles in CD4 super( +) and CD8 super( +) T cells during antiviral immunity.