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

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 4

STIM1 and STIM2 are required for CD4+ T cell help to maintain memory CD8+ T cells.

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STIM1 and STIM2 are required for CD4+ T cell help to maintain memory CD8...
(A–D) WT CD4+ T cells restore the maintenance of DKO memory CD8+ T cells. (A) Generation of WT:Cd8a–/– and DKO:Cd8a–/– chimeras. (B–D) Chimeras were infected with LCMVARM and analyzed 60 days p.i. for the frequencies (B) and absolute numbers (C) of LCMV-specific CD8+ T cells (mean ± SEM of cells from 6 WT and 6 DKO chimeras). (D) Intracellular cytokine staining for IL-2 and IFN-γ in splenic CD8+ T cells isolated from chimeras 60 days p.i. and restimulated with GP33–41 peptide for 5 hours in vitro. (E–L) WT CD8+ T cells require STIM1/2-dependent CD4+ T cell help for memory maintenance. (E) 5 × 104 WT P14 T cells (Thy1.1) were adoptively transferred into congenic WT or DKO mice and simultaneously infected with LCMVARM. (F–H) Frequencies of Thy1.1+KLRG1–CD127+ memory P14 T cells in the blood 8–60 days p.i. Bar graphs show the means ± SEM. (I and J) Frequencies (I) and total numbers (J) of splenic effector and memory subsets of Thy1.1+ WT P14 T cells 60 days p.i. (K) Serum LCMV titers. Each circle represents 1 mouse; horizontal lines represent the mean viral titers. (L) Tim-3 and PD-1 expression on splenic P14 T cells. Data in F–L are from 6 WT and 5 DKO mice. Statistical significance was calculated by Student’s t test (**P < 0.01; ***P < 0.001). Numbers in FACS plots represent percentages. Green boxes in B and F–H highlight memory CD8+ T cell populations.