and [CD8.sup.+] T cell-dependent antiviral immunity requires STIM1 and STIM2

Calcium signaling is critical for lymphocyte function, and intracellular [Ca.sup.2+] concentrations are regulated by store-operated [Ca.sup.2+] entry (SOCE) through [Ca.sup.2+] release-activated [Ca.sup.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 Stiml and its homolog Stim2 in T cells, we determined that both components are required for the maintenance of virus-specific memory [CD8.sup.+] 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.sup.+] T cells into fully functional cytolytic effector cells and mediated the production of cytokines and prevented cellular exhaustion in viral-specific [CD8.sup.+] effector T cells. Importantly, memory and recall responses by [CD8.sup.+] T cells required expression of STIM1 and STIM2 in [CD4.sup.+] T cells. [CD4.sup.+] T cells lacking STIM1 and STIM2 were unable to provide "help" to [CD8.sup.+] 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.sup.+] and [CD8.sup.+] T cells during antiviral immunity.