(ACC) Impaired recall response in DKO mice

(ACC) Impaired recall response in DKO mice. cells into fully functional cytolytic effector cells and mediated the production of cytokines and prevented cellular exhaustion in viral-specific CD8+ effector T cells. Importantly, memory and recall responses by CD8+ T cells required expression of STIM1 and STIM2 in CD4+ T cells. CD4+ T cells lacking STIM1 and STIM2 were unable to provide help to CD8+ T cells due to aberrant regulation of CD40L expression. Together, our data indicate that STIM1, STIM2, and CRAC channel function play distinct but synergistic functions in CD4+ and CD8+ T cells during antiviral immunity. Introduction Ca2+ signals play an important role in the function of CD4+ and CD8+ T cells (1, 2). Intracellular Ca2+ concentrations in T cells are predominantly regulated through Ca2+ releaseCactivated Ca2+ (CRAC) channels in the plasma membrane (3, 4). CRAC channels are activated following T cell receptor (TCR) engagement, which leads to the activation of phospholipase C, production of 1 1,4,5-inositol trisphosphate (IP3), and release of Ca2+ from ER Ca2+ stores via the opening of IP3 receptor channels. Ca2+ release, however, is not sufficient to sustain intracellular Ca2+ levels, cytokine production, and T cell activation (1, Anavex2-73 HCl 5). Instead, Ca2+ release activates 2 proteins located in the ER membrane, stromal conversation molecule 1 (STIM1) and STIM2, which translocate to ER plasma membrane junctions (6, 7), where they bind and open ORAI1, the pore-forming subunit of the CRAC channel (8C10). Since this form of Ca2+ influx is dependent around Anavex2-73 HCl the Ca2+ filling state of the ER, it is referred to as store-operated Ca2+ entry (SOCE) (2, 3, 11, 12). The importance of CRAC channels for lymphocyte function is usually emphasized by the severe BPES1 combined immunodeficiencyClike (SCID-like) disease in patients with mutations in and genes we characterized, whose T cells lack CRAC channel function and SOCE (8, 13C15). These patients are susceptible to recurrent and chronic viral infections, particularly those involving herpes viruses, including EBV, CMV, and human herpes virus 8 (HHV-8), which led to the development of virus-associated tumors in some patients (13, 14, 16, 17). These findings indicate an important role of CRAC channels in T cellCmediated antiviral and antitumor immunity. While T cells develop normally in ORAI1- Anavex2-73 HCl and STIM1-deficient patients and mice, their function is severely impaired. CD4+ and CD8+ T cells show reduced antigen-specific proliferation in vitro and fail to produce IL-2, IFN-, TNF-, and other cytokines (13, 18C22). We found that in cytotoxic CD8+ T cells, CRAC channels are required for controlling tumor growth in several mouse models of cancer and for tumor cell killing (23). Additionally, CRAC channels are required for the function of CD4+ T cells in vivo, as mice with T cellCspecific deletion of or genes were protected from CD4+ T cellCmediated inflammation in animal models of multiple sclerosis and colitis (20, 24, 25). How CRAC channels control antiviral immunity in vivo is poorly understood. CD8+ T cells are essential for antiviral immunity by killing virus-infected cells during the acute stages of infection and by providing long-term protection against viral infection through the generation and maintenance of memory CD8+ T cells. During an acute viral infection, naive virusCspecific CD8+ Anavex2-73 HCl T cells rapidly expand and differentiate into cytotoxic terminal effector (Teff) cells whose primary function is to kill virus-infected cells via the release of granzyme and perforin and the secretion of cytokines such as IFN- and TNF-. Teff cells are characterized by high expression levels of the killer cell lectin-like receptor G1 (KLRG1) and the transcription factor T-bet, but low levels of IL-7 receptor chain (IL-7R or CD127) (26). Following viral clearance, the Teff cell population contracts, whereas a smaller population of antigen-specific, long-lived memory CD8+ T cells persists that expresses high levels of CD127, but low levels of KLRG1 (26). The development, maintenance, and function of memory CD8+ T cells are controlled by a number of factors. These include the strength and frequency of TCR-antigen interactions (27, 28), costimulatory receptors and ligands on T cells and antigen-presenting cells (APCs), CD4+ T cell help (29, 30), cytokines (31), virus-neutralizing antibodies (32), and CD8+ T cellCintrinsic transcription factors like Eomesodermin (Eomes) (26, 33, 34). A defining trait of adaptive immunity is the rapid.