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CD4+ and CD8+ T cell–dependent antiviral immunity requires STIM1 and STIM2
Patrick J. Shaw, … , Susan M. Kaech, Stefan Feske
Patrick J. Shaw, … , Susan M. Kaech, Stefan Feske
Published August 26, 2014
Citation Information: J Clin Invest. 2014;124(10):4549-4563. https://doi.org/10.1172/JCI76602.
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Research Article

CD4+ and CD8+ T cell–dependent antiviral immunity requires STIM1 and STIM2

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Abstract

Calcium signaling is critical for lymphocyte function, and intracellular Ca2+ concentrations are regulated by store-operated Ca2+ entry (SOCE) through Ca2+ release–activated Ca2+ (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+ 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+ T 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 roles in CD4+ and CD8+ T cells during antiviral immunity.

Authors

Patrick J. Shaw, Carl Weidinger, Martin Vaeth, Kevin Luethy, Susan M. Kaech, Stefan Feske

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Figure 1

STIM1 and STIM2 in T cells control immunity to acute LCMV infection and the maintenance of virus-specific memory CD8+ T cells.

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STIM1 and STIM2 in T cells control immunity to acute LCMV infection and ...
Stim1fl/fl Stim2fl/fl Cd4-Cre (DKO) and WT mice were infected with LCMVARM (2 × 105 PFU; i.p.). (A) Viral titers in the sera and livers of mice. Each dot represents 1 mouse; horizontal lines show the means of the viral titers. ND, not detectable. (B) Representative flow cytometric plots of splenic CD8+ T cells from WT and DKO mice analyzed 8 days p.i. using DbNP396–404 and Db-GP33–41 tetramers. (C) Total numbers of LCMV-specific (DbNP396–404 tetramer+) CD8+ T cells in the spleens of WT (n = 5–9) and DKO (n = 7–9) mice at days 8, 35, and 60 p.i. (D–G) Expression of KLRG1 and CD127 (IL-7Rα) on DbNP396–404 tetramer+ splenic CD8+ T cells from WT (n = 5–9) and DKO (n = 7–9) mice (D). Total numbers of LCMV-specific terminal effector (KLRG1+CD127– in E) and memory CD8+ T cell populations (KLRG1+CD127+ in F, KLRG1–CD127+ in G). Numbers in E–G indicate fold change differences between WT and DKO mice. Numbers in dot plots in B and D represent the percentages of cells in gates. Statistical significance was calculated by Student’s t test (*P < 0.05; **P < 0.01; ***P < 0.001).
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