ORAI2 modulates store-operated calcium entry and T cell-mediated immunity

Abstract

Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels is critical for lymphocyte function and immune responses. CRAC channels are hexamers of ORAI proteins that form the channel pore, but the contributions of individual ORAI homologues to CRAC channel function are not well understood. Here we show that deletion of Orai1 reduces, whereas deletion of Orai2 increases, SOCE in mouse T cells. These distinct effects are due to the ability of ORAI2 to form heteromeric channels with ORAI1 and to attenuate CRAC channel function. The combined deletion of Orai1 and Orai2 abolishes SOCE and strongly impairs T cell function. In vivo, Orai1/Orai2 double-deficient mice have impaired T cell-dependent antiviral immune responses, and are protected from T cell-mediated autoimmunity and alloimmunity in models of colitis and graft-versus-host disease. Our study demonstrates that ORAI1 and ORAI2 form heteromeric CRAC channels, in which ORAI2 fine-tunes the magnitude of SOCE to modulate immune responses.

OMIP‐048 MC: Quantification of calcium sensors and channels expression in lymphocyte subsets by mass cytometry

“…1 to 4). Moreover, the level of ORAI1 channels expression was found to increase upon T-cell activation in CD4 Tconv and Treg, in agreement with recently published results (18). 5 to 10).…”

Store-Operated Ca2+ Entry Controls Clonal Expansion of T Cells through Metabolic Reprogramming

“…Cells were loaded with 1 μM Fura-2-AM (Molecular Probes), and washed twice with 0 mM Ca 2+ Ringer solution as described (Feske et al, 2006; Vaeth et al, 2017). Ca 2+ measurements were performed using a FlexStation 3 multi-mode microplate reader (Molecular Devices).…”

“…In T cells, Ca 2+ release-activated Ca 2+ (CRAC) channels are the main source of [Ca 2+ ] i upon TCR ligation and are critical for calcineurin activation (Feske et al, 2012). CRAC channels are located in the plasma membrane and composed of ORAI1 and ORAI2 proteins that form the Ca 2+ -permeant pore of the channel (Feske et al, 2006; Prakriya et al, 2006; Vaeth et al, 2017). They are activated upon TCR stimulation, which triggers the production of the second messenger inositol 1,4,5-trisphosphate (IP 3 ) and opening of IP 3 receptor channels in the endoplasmic reticulum (ER) (Feske, 2007).…”

“…As a consequence of abolished SOCE, the patients’ T cells fail to activate calcineurin, which results in impaired proliferation and cytokine production (Feske et al, 2012). Similar to SOCE-deficient patients, lymphocytes from mice with genetic deletion of Orai1 and Orai2 or Stim1 and Stim2 genes in T cells have impaired cytokine production and antigen-dependent proliferation that result in defective T cell-mediated immune responses (Desvignes et al, 2015; Oh-Hora et al, 2008; Shaw et al, 2014; Vaeth et al, 2016; Vaeth et al, 2017). Many of the effects of SOCE and calcineurin signaling on T cell function are mediated by transcription factors of the nuclear factor of activated T cells (NFAT) family (Feske, 2007; Muller and Rao, 2010).…”

“…Some of the proposed mechanisms involve regulation of the ‘growth factor’ interleukin-2 (IL-2) and cyclins or cyclin-dependent kinases, which in some cell types depend on calcineurin and NFAT signaling (Mognol et al, 2016). Although IL-2 promotes T cell proliferation in vitro in an auto- or paracrine fashion, addition of exogenous IL-2 to T cells from patients with null mutations in ORAI1 or STIM1 or T cells from Orai1 fl/fl Cd4Cre Orai2 −/− mice only weakly rescues TCR-induced proliferation in vitro (Feske et al, 1996; Fuchs et al, 2012; Le Deist et al, 1995; Picard et al, 2009; Schaballie et al, 2015; Vaeth et al, 2017). Another possible mechanism by which SOCE may control T cell proliferation is through the regulation of metabolism.…”