STIM1-Independent T Cell Development and Effector Function In Vivo

Abstract

Store-operated Ca2؉ entry (SOCE) is believed to be of pivotal importance in T cell physiology. To test this hypothesis, we generated mice constitutively lacking the SOCE-regulating Ca 2؉ sensor stromal interaction molecule 1 (STIM1). In vitro analyses showed that SOCE and Ag receptor complex-triggered Ca 2؉ flux into STIM1-deficient T cells is virtually abolished. In vivo, STIM1-deficient mice developed a lymphoproliferative disease despite normal thymic T cell maturation and normal frequencies of CD4 ؉ Foxp3؉ regulatory T cells. Unexpectedly, STIM1-deficient bone marrow chimeric mice mounted humoral immune responses after vaccination and STIM1-deficient T cells were capable of inducing acute graft-versus-host disease following adoptive transfer into allogeneic hosts. These results demonstrate that STIM1-dependent SOCE is crucial for homeostatic T cell proliferation, but of much lesser importance for thymic T cell differentiation or T cell effector functions.

Stromal Interaction Molecules 1 and 2 Are Key Regulators of Autoreactive T Cell Activation in Murine Autoimmune Central Nervous System Inflammation

“…The closely related STIM2 has been shown to regulate basal cytosolic and store Ca 2+ concentrations in different cell types (13). The recent generation of mice lacking STIM molecules in T cells confirmed the essential function of STIM1 for SOCE (12,14) and also revealed the contribution of STIM2 to this process (15). The significance of SOCE for T cell function in vivo, however, has not been definitively addressed to date despite the recent description of human immunodeficiency syndromes associated with deficiencies in STIM1 function (16).…”

“…The significance of SOCE for T cell function in vivo, however, has not been definitively addressed to date despite the recent description of human immunodeficiency syndromes associated with deficiencies in STIM1 function (16). A first study has revealed that STIM1-deficient T cells display defects in homeostatic T cell proliferation but, despite abolished SOCE, are able to support humoral immune responses after vaccination and can induce acute graft-versus-host disease following adoptive transfer into allogeneic hosts (12). In contrast, the significance of STIM-dependent SOCE for inflammatory reactions in vivo has remained elusive.…”

“…This Ca 2+ store depletion is followed by Ca 2+ entry through specialized Ca 2+ release-activated calcium channels in the plasma membrane, resulting in longerlasting (∼1 h) elevated cytosolic Ca 2+ concentration, which is mandatory for transcription-dependent steps of T cell activation (8,9). This so-called store-operated calcium entry (SOCE) occurs through the four-transmembrane channel, Orai1, (6,10,11) and is regulated by the endoplasmic reticulum-resident calcium sensor molecule stromal interaction molecule (STIM) 1, which connects store depletion to the opening of the channel (12). The closely related STIM2 has been shown to regulate basal cytosolic and store Ca 2+ concentrations in different cell types (13).…”

Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3 + regulatory T cells

“…S8A). nTreg can be activated and expanded by superagonistic CD28-specific mAb (CD28SA; D665) in mice (24,25). Injecting CD28SA into mice with Treg-specific inactivation of NFAT2 (Nfat2 fl/fl × FIC; Fig.…”

Store-Operated Calcium Channels: New Perspectives on Mechanism and Function

“…T cell-dependent antibody responses and graft vs. host disease response appear relatively unaffected in STIM1 2/2 mice (Beyersdorf et al 2009). Partial function of B cells is also evident in STIM1-or Orai1-deficient patients who develop lymphoproliferative disease and an autoimmune attack on their own neutrophils and thrombocytes Picard et al 2009).…”